Skip to main content

Co-signal Molecules in T-Cell Activation

Historical Overview and Perspective

  • Chapter
  • First Online:
Co-signal Molecules in T Cell Activation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1189))

Abstract

The two-signal model of T-cell activation, proposed approximately four decades ago, has undergone various refinements while maintaining its principal doctrine. Since the discovery of CD28, a variety of co-signal molecules, including co-stimulatory and co-inhibitory receptors and ligands, have been identified. These molecules fine-tune various immune responses both in the primary or secondary lymphoid tissues and in the peripheral tissues. Most co-signal receptors are expressed and induced on T cells during distinct stages (naïve/resting, activating, memory, and exhausting). These co-signaling pathways play critical and diverse roles in maintaining T-cell tolerance and eliciting T-cell immune responses in health and disease. This introductory chapter provides a historical overview of the key findings that have led to our current view of T-cell co-stimulation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772

    Article  CAS  PubMed  Google Scholar 

  • Akiba H, Oshima H, Takeda K, Atsuta M, Nakano H, Nakajima A, Nohara C, Yagita H, Okumura K (1999) CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells. J Immunol 162:7058–7066

    CAS  PubMed  Google Scholar 

  • Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ et al (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198:63–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aruffo A, Seed B (1987) Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A 84:8573–8577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azuma M, Lanier LL (1995) The role of CD28 costimulation in the generation of cytotoxic T lymphocytes. Curr Top Microbiol Immunol 198:59–74

    CAS  PubMed  Google Scholar 

  • Azuma M, Cayabyab M, Buck D, Phillips JH, Lanier LL (1992a) CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J Exp Med 175:353–360

    Article  CAS  PubMed  Google Scholar 

  • Azuma M, Cayabyab M, Buck D, Phillips JH, Lanier LL (1992b) Involvement of CD28 in MHC-unrestricted cytotoxicity mediated by a human natural killer leukemia cell line. J Immunol 149:1115–1123

    CAS  PubMed  Google Scholar 

  • Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoza C (1993) B70 antigen is a second ligand for CTLA-4 and CD28. Nature 366:76–79

    Article  CAS  PubMed  Google Scholar 

  • Baxter AG, Hodgkin PD (2002) Activation rules: the two-signal theories of immune activation. Nat Rev Immunol 2:439–446

    Article  CAS  PubMed  Google Scholar 

  • Bedoui S, Heath WR, Mueller SN (2016) CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity. Immunol Rev 272:52–64

    Article  CAS  PubMed  Google Scholar 

  • Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA (2011) Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev 241:180–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradshaw JD, Lu P, Leytze G, Rodgers J, Schieven GL, Bennett KL, Linsley PS, Kurtz SE (1997) Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry 36:15975–15982

    Article  CAS  PubMed  Google Scholar 

  • Bretscher P, Cohn M (1970) A theory of self-nonself discrimination. Science 169:1042–1049

    Article  CAS  PubMed  Google Scholar 

  • Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987) A new member of the immunoglobulin superfamily--CTLA-4. Nature 328:267–270

    Article  CAS  PubMed  Google Scholar 

  • Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 229:244–258

    Article  CAS  PubMed  Google Scholar 

  • Carreno BM, Collins M (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 20:29–53

    Article  CAS  PubMed  Google Scholar 

  • Carreno BM, Collins M (2003) BTLA: a new inhibitory receptor with a B7-like ligand. Trends Immunol 24:524–527

    Article  CAS  PubMed  Google Scholar 

  • Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (2002) PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 32:634–643

    Article  CAS  PubMed  Google Scholar 

  • Caux C, Vanbervliet B, Massacrier C, Azuma M, Okumura K, Lanier LL, Banchereau J (1994) B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells. J Exp Med 180:1841–1847

    Article  CAS  PubMed  Google Scholar 

  • Chambers CA, Allison JP (1999) Costimulatory regulation of T cell function. Curr Opin Cell Biol 11:203–210

    Article  CAS  PubMed  Google Scholar 

  • Chambers CA, Sullivan TJ, Allison JP (1997) Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7:885–895

    Article  CAS  PubMed  Google Scholar 

  • Chambers CA, Sullivan TJ, Truong T, Allison JP (1998) Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol 28:3137–3143

    Article  CAS  PubMed  Google Scholar 

  • Chambers CA, Kuhns MS, Allison JP (1999) Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A 96:8603–8608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, Chen L (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2:269–274

    Article  CAS  PubMed  Google Scholar 

  • Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945–954

    Article  CAS  PubMed  Google Scholar 

  • Chen L (2004) Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336–347

    Article  CAS  PubMed  Google Scholar 

  • Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, Zhu Y, Flies DB, Tamada K, Chen L (2003) Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol 171:4650–4654

    Article  CAS  PubMed  Google Scholar 

  • Cunningham AJ, Lafferty KJ (1977) A simple conservative explanation of the H-2 restriction of interactions between lymphocytes. Scand J Immunol 6:1–6

    Article  CAS  PubMed  Google Scholar 

  • Damle NK, Hansen JA, Good RA, Gupta S (1981) Monoclonal antibody analysis of human T lymphocyte subpopulations exhibiting autologous mixed lymphocyte reaction. Proc Natl Acad Sci U S A 78:5096–5098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dariavach P, Mattei MG, Golstein P, Lefranc MP (1988) Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 18:1901–1905

    Article  CAS  PubMed  Google Scholar 

  • DeBenedette MA, Chu NR, Pollok KE, Hurtado J, Wade WF, Kwon BS, Watts TH (1995) Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J Exp Med 181:985–992

    Article  CAS  PubMed  Google Scholar 

  • del Rio ML, Lucas CL, Buhler L, Rayat G, Rodriguez-Barbosa JI (2010) HVEM/LIGHT/BTLA/CD160 cosignaling pathways as targets for immune regulation. J Leukoc Biol 87:223–235

    Article  PubMed  CAS  Google Scholar 

  • Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369

    Article  CAS  PubMed  Google Scholar 

  • Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L (2004) B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 20:327–336

    Article  CAS  PubMed  Google Scholar 

  • Duttagupta PA, Boesteanu AC, Katsikis PD (2009) Costimulation signals for memory CD8+ T cells during viral infections. Crit Rev Immunol 29:469–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fife BT, Guleria I, Gubbels Bupp M, Eagar TN, Tang Q, Bour-Jordan H, Yagita H, Azuma M, Sayegh MH, Bluestone JA (2006) Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203:2737–2747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA (2009) Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10:1185–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freeman GJ, Borriello F, Hodes RJ, Reiser H, Gribben JG, Ng JW, Kim J, Goldberg JM, Hathcock K, Laszlo G et al (1993a) Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med 178:2185–2192

    Article  CAS  PubMed  Google Scholar 

  • Freeman GJ, Borriello F, Hodes RJ, Reiser H, Hathcock KS, Laszlo G, McKnight AJ, Kim J, Du L, Lombard DB et al (1993b) Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science 262:907–909

    Article  CAS  PubMed  Google Scholar 

  • Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA Jr, Lombard LA, Gray GS, Nadler LM (1993c) Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 262:909–911

    Article  CAS  PubMed  Google Scholar 

  • Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gimmi CD, Freeman GJ, Gribben JG, Sugita K, Freedman AS, Morimoto C, Nadler LM (1991) B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci U S A 88:6575–6579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gimmi CD, Freeman GJ, Gribben JG, Gray G, Nadler LM (1993) Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci U S A 90:6586–6590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldberg MV, Maris CH, Hipkiss EL, Flies AS, Zhen L, Tuder RM, Grosso JF, Harris TJ, Getnet D, Whartenby KA et al (2007) Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 110:186–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez LC, Loyet KM, Calemine-Fenaux J, Chauhan V, Wranik B, Ouyang W, Eaton DL (2005) A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc Natl Acad Sci U S A 102:1116–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodwin RG, Din WS, Davis-Smith T, Anderson DM, Gimpel SD, Sato TA, Maliszewski CR, Brannan CI, Copeland NG, Jenkins NA et al (1993) Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immunol 23:2631–2641

    Article  CAS  PubMed  Google Scholar 

  • Gratz IK, Rosenblum MD, Abbas AK (2013) The life of regulatory T cells. Ann N Y Acad Sci 1283:8–12

    Article  CAS  PubMed  Google Scholar 

  • Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548

    Article  PubMed  CAS  Google Scholar 

  • Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, Eibel H, Fischer B, Schaffer AA, Mages HW et al (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268

    Article  CAS  PubMed  Google Scholar 

  • Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101

    Article  CAS  PubMed  Google Scholar 

  • Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, Sayegh MH, Guleria I (2007) A link between PDL1 and T regulatory cells in fetomaternal tolerance. J Immunol 179:5211–5219

    Article  CAS  PubMed  Google Scholar 

  • Hara T, Fu SM, Hansen JA (1985) Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). J Exp Med 161:1513–1524

    Article  CAS  PubMed  Google Scholar 

  • Harding FA, Allison JP (1993) CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help. J Exp Med 177:1791–1796

    Article  CAS  PubMed  Google Scholar 

  • Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356:607–609

    Article  CAS  PubMed  Google Scholar 

  • Harper K, Balzano C, Rouvier E, Mattei MG, Luciani MF, Golstein P (1991) CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 147:1037–1044

    CAS  PubMed  Google Scholar 

  • Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci U S A 105:10495–10500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hurtado JC, Kim SH, Pollok KE, Lee ZH, Kwon BS (1995) Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28. J Immunol 155:3360–3367

    CAS  PubMed  Google Scholar 

  • Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266

    Article  CAS  PubMed  Google Scholar 

  • Igarashi H, Cao Y, Iwai H, Piao J, Kamimura Y, Hashiguchi M, Amagasa T, Azuma M (2008) GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells. Biochem Biophys Res Commun 369:1134–1138

    Article  CAS  PubMed  Google Scholar 

  • Inaba K, Witmer-Pack M, Inaba M, Hathcock KS, Sakuta H, Azuma M, Yagita H, Okumura K, Linsley PS, Ikehara S et al (1994) The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med 180:1849–1860

    Article  CAS  PubMed  Google Scholar 

  • Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T (2003) PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 198:39–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jenkins MK, Schwartz RH (1987) Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 165:302–319

    Article  CAS  PubMed  Google Scholar 

  • Jenkins MK, Pardoll DM, Mizuguchi J, Quill H, Schwartz RH (1987) T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev 95:113–135

    Article  CAS  PubMed  Google Scholar 

  • Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, Park S, Javinal V, Chiu H, Irving B et al (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26:923–937

    Article  CAS  PubMed  Google Scholar 

  • Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM et al (2008) Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205:2763–2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • June CH, Ledbetter JA, Gillespie MM, Lindsten T, Thompson CB (1987) T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol 7:4472–4481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • June CH, Ledbetter JA, Linsley PS, Thompson CB (1990) Role of the CD28 receptor in T-cell activation. Immunol Today 11:211–216

    Article  CAS  PubMed  Google Scholar 

  • Jung G, Ledbetter JA, Muller-Eberhard HJ (1987) Induction of cytotoxicity in resting human T lymphocytes bound to tumor cells by antibody heteroconjugates. Proc Natl Acad Sci U S A 84:4611–4615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, Sakaguchi S, Ishikawa I, Azuma M (2004) Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol 172:7306–7314

    Article  CAS  PubMed  Google Scholar 

  • Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, Jenkins MK (1995) Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol 155:1032–1036

    CAS  PubMed  Google Scholar 

  • Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 203:883–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinnear G, Wood KJ, Fallah-Arani F, Jones ND (2013) A diametric role for OX40 in the response of effector/memory CD4+ T cells and regulatory T cells to alloantigen. J Immunol 191:1465–1475

    Article  CAS  PubMed  Google Scholar 

  • Kobori H, Hashiguchi M, Piao J, Kato M, Ritprajak P, Azuma M (2010) Enhancement of effector CD8+ T-cell function by tumour-associated B7-H3 and modulation of its counter-receptor triggering receptor expressed on myeloid cell-like transcript 2 at tumour sites. Immunology 130:363–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kojima R, Kajikawa M, Shiroishi M, Kuroki K, Maenaka K (2011) Molecular basis for herpesvirus entry mediator recognition by the human immune inhibitory receptor CD160 and its relationship to the cosignaling molecules BTLA and LIGHT. J Mol Biol 413:762–772

    Article  CAS  PubMed  Google Scholar 

  • Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M (2016) Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol 57:54–60

    Article  CAS  PubMed  Google Scholar 

  • Korman AJ, Peggs KS, Allison JP (2006) Checkpoint blockade in cancer immunotherapy. Adv Immunol 90:297–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krummel MF, Sullivan TJ, Allison JP (1996) Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo. Int Immunol 8:519–523

    Article  CAS  PubMed  Google Scholar 

  • Kuipers H, Muskens F, Willart M, Hijdra D, van Assema FB, Coyle AJ, Hoogsteden HC, Lambrecht BN (2006) Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 36:2472–2482

    Article  CAS  PubMed  Google Scholar 

  • Lafage-Pochitaloff M, Costello R, Couez D, Simonetti J, Mannoni P, Mawas C, Olive D (1990) Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33-q34. Immunogenetics 31:198–201

    Article  CAS  PubMed  Google Scholar 

  • Lafferty KJ, Cunningham AJ (1975) A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci 53:27–42

    Article  CAS  PubMed  Google Scholar 

  • Lanier LL, O’Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M (1995) CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol 154:97–105

    CAS  PubMed  Google Scholar 

  • Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    Article  CAS  PubMed  Google Scholar 

  • Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA (1998) Molecular basis of T cell inactivation by CTLA-4. Science 282:2263–2266

    Article  CAS  PubMed  Google Scholar 

  • Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, Miller J, Bluestone JA (1993) Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci U S A 90:11054–11058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lesslauer W, Koning F, Ottenhoff T, Giphart M, Goulmy E, van Rood JJ (1986) T90/44 (9.3 antigen). A cell surface molecule with a function in human T cell activation. Eur J Immunol 16:1289–1296

    Article  CAS  PubMed  Google Scholar 

  • Lindstein T, June CH, Ledbetter JA, Stella G, Thompson CB (1989) Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science 244:339–343

    Article  CAS  PubMed  Google Scholar 

  • Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA (1991a) Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 173:721–730

    Article  CAS  PubMed  Google Scholar 

  • Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA (1991b) CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561–569

    Article  CAS  PubMed  Google Scholar 

  • Linsley PS, Greene JL, Tan P, Bradshaw J, Ledbetter JA, Anasetti C, Damle NK (1992a) Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med 176:1595–1604

    Article  CAS  PubMed  Google Scholar 

  • Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA (1992b) Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257:792–795

    Article  CAS  PubMed  Google Scholar 

  • Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS (1996) Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 4:535–543

    Article  CAS  PubMed  Google Scholar 

  • Mak TW, Shahinian A, Yoshinaga SK, Wakeham A, Boucher LM, Pintilie M, Duncan G, Gajewska BU, Gronski M, Eriksson U et al (2003) Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat Immunol 4:765–772

    Article  CAS  PubMed  Google Scholar 

  • Mallett S, Fossum S, Barclay AN (1990) Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes--a molecule related to nerve growth factor receptor. EMBO J 9:1063–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW (1996) Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272:1170–1173

    Article  CAS  PubMed  Google Scholar 

  • Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M, Hammerbeck CD, Popescu F, Xiao Z (2006) Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev 211:81–92

    Article  CAS  PubMed  Google Scholar 

  • Morris AB, Adams LE, Ford ML (2018) Influence of T cell Coinhibitory molecules on CD8(+) recall responses. Front Immunol 9:1810

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nakajima A, Azuma M, Kodera S, Nuriya S, Terashi A, Abe M, Hirose S, Shirai T, Yagita H, Okumura K (1995) Preferential dependence of autoantibody production in murine lupus on CD86 costimulatory molecule. Eur J Immunol 25:3060–3069

    Article  CAS  PubMed  Google Scholar 

  • Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol 15:45–56

    Article  CAS  PubMed  Google Scholar 

  • Nishimura H, Minato N, Nakano T, Honjo T (1998) Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 10:1563–1572

    Article  CAS  PubMed  Google Scholar 

  • Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    Article  CAS  PubMed  Google Scholar 

  • Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    Article  CAS  PubMed  Google Scholar 

  • Nuriya S, Yagita H, Okumura K, Azuma M (1996) The differential role of CD86 and CD80 co-stimulatory molecules in the induction and the effector phases of contact hypersensitivity. Int Immunol 8:917–926

    Article  CAS  PubMed  Google Scholar 

  • Ohshima Y, Yang LP, Uchiyama T, Tanaka Y, Baum P, Sergerie M, Hermann P, Delespesse G (1998) OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors. Blood 92:3338–3345

    Article  CAS  PubMed  Google Scholar 

  • Oikawa T, Kamimura Y, Akiba H, Yagita H, Okumura K, Takahashi H, Zeniya M, Tajiri H, Azuma M (2006) Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease. J Immunol 177:4281–4287

    Article  CAS  PubMed  Google Scholar 

  • Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 98:13866–13871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okazaki T, Okazaki IM, Wang J, Sugiura D, Nakaki F, Yoshida T, Kato Y, Fagarasan S, Muramatsu M, Eto T et al (2011) PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med 208:395–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okoye IS, Houghton M, Tyrrell L, Barakat K, Elahi S (2017) Coinhibitory receptor expression and immune checkpoint blockade: maintaining a balance in CD8(+) T cell responses to chronic viral infections and Cancer. Front Immunol 8:1215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21:401–413

    Article  CAS  PubMed  Google Scholar 

  • Pollok KE, Kim YJ, Zhou Z, Hurtado J, Kim KK, Pickard RT, Kwon BS (1993) Inducible T cell antigen 4-1BB. Analysis of expression and function. J Immunol 150:771–781

    CAS  PubMed  Google Scholar 

  • Prasad DV, Richards S, Mai XM, Dong C (2003) B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18:863–873

    Article  CAS  PubMed  Google Scholar 

  • Rao M, Valentini D, Dodoo E, Zumla A, Maeurer M (2017) Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm. Int J Infect Dis 56:221–228

    Article  CAS  PubMed  Google Scholar 

  • Ritprajak P, Azuma M (2015) Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol 51:221–228

    Article  CAS  PubMed  Google Scholar 

  • Ritprajak P, Hashiguchi M, Tsushima F, Chalermsarp N, Azuma M (2010) Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses. J Immunol 184:4918–4925

    Article  CAS  PubMed  Google Scholar 

  • Rudd CE (2008) The reverse stop-signal model for CTLA4 function. Nat Rev Immunol 8:153–160

    Article  CAS  PubMed  Google Scholar 

  • Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ (2003) Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 198:71–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schildberg FA, Klein SR, Freeman GJ, Sharpe AH (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44:955–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, Wei B, Hogg N, Garside P, Rudd CE (2006) Reversal of the TCR stop signal by CTLA-4. Science 313:1972–1975

    Article  CAS  PubMed  Google Scholar 

  • Schwartz RH (1990) A cell culture model for T lymphocyte clonal anergy. Science 248:1349–1356

    Article  CAS  PubMed  Google Scholar 

  • Schwartz RH (1992) Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 71:1065–1068

    Article  CAS  PubMed  Google Scholar 

  • Sedy JR, Gavrieli M, Potter KG, Hurchla MA, Lindsley RC, Hildner K, Scheu S, Pfeffer K, Ware CF, Murphy TL, Murphy KM (2005) B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol 6:90–98

    Article  CAS  PubMed  Google Scholar 

  • Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D (2004) PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574:37–41

    Article  CAS  PubMed  Google Scholar 

  • Shiratori T, Miyatake S, Ohno H, Nakaseko C, Isono K, Bonifacino JS, Saito T (1997) Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6:583–589

    Article  CAS  PubMed  Google Scholar 

  • Shuford WW, Klussman K, Tritchler DD, Loo DT, Chalupny J, Siadak AW, Brown TJ, Emswiler J, Raecho H, Larsen CP et al (1997) 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J Exp Med 186:47–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L (2003) B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18:849–861

    Article  CAS  PubMed  Google Scholar 

  • Smith KM, Brewer JM, Webb P, Coyle AJ, Gutierrez-Ramos C, Garside P (2003) Inducible costimulatory molecule-B7-related protein 1 interactions are important for the clonal expansion and B cell helper functions of naive, Th1, and Th2 T cells. J Immunol 170:2310–2315

    Article  CAS  PubMed  Google Scholar 

  • Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, Duncan GS, Bukczynski J, Plyte S, Elia A et al (2003) The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 4:899–906

    Article  CAS  PubMed  Google Scholar 

  • Sun B, Zhang Y (2014) Overview of orchestration of CD4+ T cell subsets in immune responses. Adv Exp Med Biol 841:1–13

    Article  CAS  PubMed  Google Scholar 

  • Sun M, Richards S, Prasad DV, Mai XM, Rudensky A, Dong C (2002) Characterization of mouse and human B7-H3 genes. J Immunol 168:6294–6297

    Article  CAS  PubMed  Google Scholar 

  • Tan JT, Whitmire JK, Ahmed R, Pearson TC, Larsen CP (1999) 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses. J Immunol 163:4859–4868

    CAS  PubMed  Google Scholar 

  • Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF et al (2007) PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection. J Immunol 179:5204–5210

    Article  CAS  PubMed  Google Scholar 

  • Thompson CB, Allison JP (1997) The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445–450

    Article  CAS  PubMed  Google Scholar 

  • Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547

    Article  CAS  PubMed  Google Scholar 

  • Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H (2003) Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A 100:15059–15064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H (2001) B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 193:839–846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valbon SF, Condotta SA, Richer MJ (2016) Regulation of effector and memory CD8(+) T cell function by inflammatory cytokines. Cytokine 82:16–23

    Article  CAS  PubMed  Google Scholar 

  • Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP (2005) Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105:2845–2851

    Article  CAS  PubMed  Google Scholar 

  • Vu MD, Xiao X, Gao W, Degauque N, Chen M, Kroemer A, Killeen N, Ishii N, Li XC (2007) OX40 costimulation turns off Foxp3+ Tregs. Blood 110:2501–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L (2000) Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood 96:2808–2813

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, Lu LF, Gondek D, Wang Y, Fava RA et al (2011) VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 208:577–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward-Kavanagh LK, Lin WW, Sedy JR, Ware CF (2016) The TNF receptor superfamily in co-stimulating and co-inhibitory responses. Immunity 44:1005–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X et al (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4:670–679

    Article  CAS  PubMed  Google Scholar 

  • Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988

    Article  CAS  PubMed  Google Scholar 

  • Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K et al (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545

    Article  CAS  PubMed  Google Scholar 

  • Yi KH, Chen L (2009) Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev 229:145–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T (2012) Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 209:1201–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B, Tom I, Ivelja S, Refino CJ, Clark H et al (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10:48–57

    Article  CAS  PubMed  Google Scholar 

  • Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP (2003) B7x: a widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci U S A 100:10388–10392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Borges CM, Fan MY, Harris JE, Turka LA (2015) Requirement for CD28 in effector regulatory T cell differentiation, CCR6 induction, and skin homing. J Immunol 195:4154–4161

    Article  CAS  PubMed  Google Scholar 

  • Zhu Y, Yao S, Chen L (2011) Cell surface signaling molecules in the control of immune responses: a tide model. Immunity 34:466–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Miyuki Azuma .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Azuma, M. (2019). Co-signal Molecules in T-Cell Activation. In: Azuma, M., Yagita, H. (eds) Co-signal Molecules in T Cell Activation. Advances in Experimental Medicine and Biology, vol 1189. Springer, Singapore. https://doi.org/10.1007/978-981-32-9717-3_1

Download citation

Publish with us

Policies and ethics