Abstract
Although many studies of intraepithelial lymphocytes (IELs) have been reported, most of them have focused on αβ-IELs; little attention has been paid to γδ-IELs. The function of γδ-IELs remains largely unclear. In this article, we briefly review a number of reports on γδ-IELs, especially those in the small intestine, along with our recent studies. We found that γδ-IELs are the most abundant (comprising >70 % of the) IELs in the duodenum and the jejunum, implying that it is absolutely necessary to investigate the function(s) of γδ-IELs when attempting to delineate the in vivo defense system of the small intestine. Intraperitoneal injection of anti-CD3 mAb stimulated the γδ-IELs and caused rapid degranulation of them. Granzyme B released from their granules induced DNA fragmentation of duodenal and jejunal epithelial cells (paracrine) and of the IELs themselves (autocrine). However, perforin (Pfn) was not detected, and DNA fragmentation was induced even in Pfn-knockout mice; our system was therefore found to present a novel type of in vivo Pfn-independent DNA fragmentation. We can therefore consider γδ-IELs to be a novel type of large granular lymphocyte without Pfn. Fragmented DNA was repaired in the cells, indicating that DNA fragmentation alone cannot be regarded as an unambiguous marker of cell death or apoptosis. Finally, since the response was so rapid and achieved without the need for accessory cells, it seems that γδ-IELs respond readily to various stimuli, are activated only once, and die 2–3 days after activation in situ without leaving their site. Taken together, these results suggest that γδ-IELs are not involved in the recognition of specific antigen(s) and are not involved in the resulting specific killing or exclusion of the relevant antigen(s).
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References
Allison JP, Havran WL (1991) The immunobiology of T cells with invariant gamma delta antigen receptors. Annu Rev Immunol 9:679–705
Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G (2001) Nuclear retention of ATM at sites of DNA double strand breaks. J Biol Chem 276:38224–38230
Baker MB, Altman NH, Podack ER, Levy RB (1996) The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med 183:2645–2656
Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401–409
Beagley KW, Husband AJ (1998) Intraepithelial lymphocytes: origins, distribution, and function. Crit Rev Immunol 18:237–254
Beagley KW, Fujihashi K, Lagoo AS, Lagoo-Deenadaylan S, Black CA, Murray AM, Sharmanov AT, Yamamoto M, McGhee JR, Elson CO et al (1995) Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine. J Immunol 154:5611–5619
Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 266:1253–1255
Bos JD, Teunissen MB, Cairo I, Krieg SR, Kapsenberg ML, Das PK, Borst J (1990) T-cell receptor gamma delta bearing cells in normal human skin. J Invest Dermatol 94:37–42
Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D (1991) Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 6:791–798
Camerini V, Panwala C, Kronenberg M (1993) Regional specialization of the mucosal immune system. Intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine. J Immunol 151:1765–1776
Chamberlain CM, Ang LS, Boivin WA, Cooper DM, Williams SJ, Zhao H, Hendel A, Folkesson M, Swedenborg J, Allard MF, McManus BM, Granville DJ (2010) Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm. Am J Pathol 176:1038–1049
Chang JS, Ocvirk S, Berger E, Kisling S, Binder U, Skerra A, Lee AS, Haller D (2012) Endoplasmic reticulum stress response promotes cytotoxic phenotype of CD8αβ+ intraepithelial lymphocytes in a mouse model for Crohn’s disease-like ileitis. J Immunol 189:1510–1520
Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R (2002) Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci 99:14338–14343
Chieppa M, Rescigno M, Huang AY, Germain RN (2006) Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J Exp Med 203:2841–2852
Choy JC, Hung VH, Hunter AL, Cheung PK, Motyka B, Goping IS, Sawchuk T, Bleackley RC, Podor TJ, McManus BM, Granville DJ (2004) Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation. Arterioscler Thromb Vasc Biol 24:2245–2250
Choy JC, Cruz RP, Kerjner A, Geisbrecht J, Sawchuk T, Fraser SA, Hudig D, Bleackley RC, Jirik FR, McManus BM, Granville DJ (2005) Granzyme B induces endothelial cell apoptosis and contributes to the development of transplant vascular disease. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 5:494–499
Corazza N, Muller S, Brunner T, Kagi D, Mueller C (2000) Differential contribution of Fas- and perforin-mediated mechanisms to the cell-mediated cytotoxic activity of naive and in vivo-primed intestinal intraepithelial lymphocytes. J Immunol 164:398–403
Darlington D, Rogers AW (1966) Epithelial lymphocytes in the small intestine of the mouse. J Anat 100:813–830
Dressel R, Raja SM, Honing S, Seidler T, Froelich CJ, von Figura K, Gunther E (2004) Granzyme-mediated cytotoxicity does not involve the mannose 6-phosphate receptors on target cells. J Biol Chem 279:20200–20210
Ebert LM, Meuter S, Moser B (2006) Homing and function of human skin gammadelta T cells and NK cells: relevance for tumor surveillance. J Immunol 176:4331–4336
Edelblum KL, Shen L, Weber CR, Marchiando AM, Clay BS, Wang Y, Prinz I, Malissen B, Sperling AI, Turner JR (2012) Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. Proc Natl Acad Sci 109:7097–7102
Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605–611
Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ (2007) Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26:798–811
Ferguson A (1977) Intraepithelial lymphocytes of the small intestine. Gut 18:921–937
Fernandez-Capetillo O, Allis CD, Nussenzweig A (2004) Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med 199:1671–1677
Foster CA, Yokozeki H, Rappersberger K, Koning F, Volc-Platzer B, Rieger A, Coligan JE, Wolff K, Stingl G (1990) Human epidermal T cells predominantly belong to the lineage expressing alpha/beta T cell receptor. J Exp Med 171:997–1013
Frank-Vaillant M, Marcand S (2002) Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol Cell 10:1189–1199
Froelich CJ, Orth K, Turbov J, Seth P, Gottlieb R, Babior B, Shah GM, Bleackley RC, Dixit VM, Hanna W (1996) New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J Biol Chem 271:29073–29079
Frossard CP, Asigbetse KE, Burger D, Eigenmann PA (2015) Gut T cell receptor-γδ(+) intraepithelial lymphocytes are activated selectively by cholera toxin to break oral tolerance in mice. Clin Exp Immunol 180:118–130
Fujihashi K, Taguchi T, Aicher WK, McGhee JR, Bluestone JA, Eldridge JH, Kiyono H (1992) Immunoregulatory functions for murine intraepithelial lymphocytes: gamma/delta T cell receptor-positive (TCR +) T cells abrogate oral tolerance, while alpha/beta TCR+ T cells provide B cell help. J Exp Med 175:695–707
Fujihashi K, Dohi T, Kweon MN, McGhee JR, Koga T, Cooper MD, Tonegawa S, Kiyono H (1999) Gammadelta T cells regulate mucosally induced tolerance in a dose-dependent fashion. Int Immunol 11:1907–1916
Goodman T, Lefrancois L (1988) Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333:855–858
Guy-Grand D, Griscelli C, Vassalli P (1978) The mouse gut T lymphocyte, a novel type of T cell. Nature, origin, and traffic in mice in normal and graft-versus-host conditions. J Exp Med 148:1661–1677
Guy-Grand D, Cerf-Bensussan N, Malissen B, Malassis-Seris M, Briottet C, Vassalli P (1991a) Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J Exp Med 173:471–481
Guy-Grand D, Malassis-Seris M, Briottet C, Vassalli P (1991b) Cytotoxic differentiation of mouse gut thymodependent and independent intraepithelial T lymphocytes is induced locally. Correlation between functional assays, presence of perforin and granzyme transcripts, and cytoplasmic granules. J Exp Med 173:1549–1552
Guy-Grand D, DiSanto JP, Henchoz P, Malassis-Seris M, Vassalli P (1998) Small bowel enteropathy: role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal. Eur J Immunol 28:730–744
Guy-Grand D, Vassalli P, Eberl G, Pereira P, Burlen-Defranoux O, Lemaitre F, Di Santo JP, Freitas AA, Cumano A, Bandeira A (2013) Origin, trafficking, and intraepithelial fate of gut-tropic T cells. J Exp Med 210:1839–1854
Halvorsen R, Leivestad T, Gaudernack G, Thorsby E (1988) Role of accessory cells in the activation of pure T cells via the T cell receptor-CD3 complex or with phytohaemagglutinin. Scand J Immunol 27:555–563
Havran WL, Jameson JM, Witherden DA (2005) Epithelial cells and their neighbors. III. Interactions between intraepithelial lymphocytes and neighboring epithelial cells. Am J Physiol Gastrointest Liver Physiol 289:G627–G630
Hayday A, Theodoridis E, Ramsburg E, Shires J (2001) Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat Immunol 2:997–1003
Holoshitz J, Romzek NC, Jia Y, Wagner L, Vila LM, Chen SJ, Wilson JM, Karp DR (1993) MHC-independent presentation of mycobacteria to human gamma delta T cells. Int Immunol 5:1437–1443
Holtmeier W, Pfander M, Hennemann A, Zollner TM, Kaufmann R, Caspary WF (2001) The TCR-delta repertoire in normal human skin is restricted and distinct from the TCR-delta repertoire in the peripheral blood. J Invest Dermatol 116:275–280
Inagaki-Ohara K, Chinen T, Matsuzaki G, Sasaki A, Sakamoto Y, Hiromatsu K, Nakamura-Uchiyama F, Nawa Y, Yoshimura A (2004) Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. J Immunol 173:1390–1398
Ishikawa H, Li Y, Abeliovich A, Yamamoto S, Kaufmann SH, Tonegawa S (1993) Cytotoxic and interferon gamma-producing activities of gamma delta T cells in the mouse intestinal epithelium are strain dependent. Proc Natl Acad Sci 90:8204–8208
Ismail AS, Behrendt CL, Hooper LV (2009) Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J Immunol 182:3047–3054
Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, Ruhn KA, Hou B, DeFranco AL, Yarovinsky F, Hooper LV (2011) Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci 108:8743–8748
Itohara S, Farr AG, Lafaille JJ, Bonneville M, Takagaki Y, Haas W, Tonegawa S (1990) Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343:754–757
Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23:687–696
Jameson J, Havran WL (2007) Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev 215:114–122
Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, Boismenu R, Havran WL (2002) A role for skin gammadelta T cells in wound repair. Science 296:747–749
Jameson JM, Cauvi G, Witherden DA, Havran WL (2004) A keratinocyte-responsive gamma delta TCR is necessary for dendritic epidermal T cell activation by damaged keratinocytes and maintenance in the epidermis. J Immunol 172:3573–3579
Jameson JM, Cauvi G, Sharp LL, Witherden DA, Havran WL (2005) Gammadelta T cell-induced hyaluronan production by epithelial cells regulates inflammation. J Exp Med 201:1269–1279
Janeway CA Jr, Jones B, Hayday A (1988) Specificity and function of T cells bearing gamma delta receptors. Immunol Today 9:73–76
Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37
Ke Y, Pearce K, Lake JP, Ziegler HK, Kapp JA (1997) Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance. J Immunol 158:3610–3618
Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27:247–254
King A, Loke YW (1990) Uterine large granular lymphocytes: a possible role in embryonic implantation? Am J Obstet Gynecol 162:308–310
King DP, Hyde DM, Jackson KA, Novosad DM, Ellis TN, Putney L, Stovall MY, Van Winkle LS, Beaman BL, Ferrick DA (1999) Cutting edge: protective response to pulmonary injury requires gamma delta T lymphocytes. J Immunol 162:5033–5036
Komano H, Fujiura Y, Kawaguchi M, Matsumoto S, Hashimoto Y, Obana S, Mombaerts P, Tonegawa S, Yamamoto H, Itohara S et al (1995) Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc Natl Acad Sci 92:6147–6151
Komori HK, Meehan TF, Havran WL (2006) Epithelial and mucosal gamma delta T cells. Curr Opin Immunol 18:534–538
Laky K, Lefrancois L, Lingenheld EG, Ishikawa H, Lewis JM, Olson S, Suzuki K, Tigelaar RE, Puddington L (2000) Enterocyte expression of interleukin 7 induces development of gammadelta T cells and Peyer’s patches. J Exp Med 191:1569–1580
Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308:551–554
Lee JH, Paull TT (2006) Purification and biochemical characterization of ataxia-telangiectasia mutated and Mre11/Rad50/Nbs1. Methods Enzymol 408:529–539
Lee JH, Paull TT (2007) Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26:7741–7748
Lee SH, Bar-Haim E, Machlenkin A, Goldberger O, Volovitz I, Vadai E, Tzehoval E, Eisenbach L (2004) In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL. Cancer Gene Ther 11:237–248
Lin T, Brunner T, Tietz B, Madsen J, Bonfoco E, Reaves M, Huflejt M, Green DR (1998) Fas ligand-mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease. J Clin Investig 101:570–577
Lowin B, Hahne M, Mattmann C, Tschopp J (1994) Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370:650–652
Mayrhofer G (1980) Thymus-dependent and thymus-independent subpopulations of intestinal intraepithelial lymphocytes: a granular subpopulation of probable bone marrow origin and relationship to mucosal mast cells. Blood 55:532–535
Mengel J, Cardillo F, Aroeira LS, Williams O, Russo M, Vaz NM (1995) Anti-gamma delta T cell antibody blocks the induction and maintenance of oral tolerance to ovalbumin in mice. Immunol Lett 48:97–102
Mollick JA, Cook RG, Rich RR (1989) Class II MHC molecules are specific receptors for staphylococcus enterotoxin A. Science 244:817–820
Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H, Bloom BR, Golan DE, Brenner MB (1995) Direct presentation of nonpeptide prenyl pyrophosphate antigens to human gamma delta T cells. Immunity 3:495–507
Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC (2000) Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103:491–500
Mowat AM (2003) Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 3:331–341
Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258
Ogata M, Oomori T, Soga H, Ota Y, Itoh A, Matsutani T, Nanno M, Suzuki R, Itoh T (2009) DNA repair after DNA fragmentation in mouse small intestinal epithelial cells. Cell Tissue Res 335:371–382
Ogata M, Ota Y, Matsutani T, Nanno M, Suzuki R, Itoh T (2013) Granzyme B-dependent and perforin-independent DNA fragmentation in intestinal epithelial cells induced by anti-CD3 mAb-activated intra-epithelial lymphocytes. Cell Tissue Res 352:287–300
Ogata M, Ota Y, Nanno M, Suzuki R, Itoh T (2014) Activation of intra-epithelial lymphocytes; their morphology, marker expression and ultimate fate. Cell Tissue Res 356:217–230
Ogata M, Ota Y, Nanno M, Suzuki R, Itoh T (2015) Autocrine DNA fragmentation of intra-epithelial lymphocytes (IELs) in mouse small intestine. Cell Tissue Res 361:799–810
Pabst O, Bernhardt G (2010) The puzzle of intestinal lamina propria dendritic cells and macrophages. Eur J Immunol 40:2107–2111
Panja A, Blumberg RS, Balk SP, Mayer L (1993) CD1d is involved in T cell-intestinal epithelial cell interactions. J Exp Med 178:1115–1119
Penney L, Kilshaw PJ, MacDonald TT (1995) Regional variation in the proliferative rate and lifespan of alpha beta TCR+ and gamma delta TCR+ intraepithelial lymphocytes in the murine small intestine. Immunology 86:212–218
Pereira P, Gerber D, Huang SY, Tonegawa S (1995) Ontogenic development and tissue distribution of V gamma 1-expressing gamma/delta T lymphocytes in normal mice. J Exp Med 182:1921–1930
Porcelli S, Brenner MB, Band H (1991) Biology of the human gamma delta T-cell receptor. Immunol Rev 120:137–183
Rapp A, Greulich KO (2004) After double-strand break induction by UV-A, homologous recombination and nonhomologous end joining cooperate at the same DSB if both systems are available. J Cell Sci 117:4935–4945
Regnier-Vigouroux A, Blanc D, Pont S, Marchetto S, Pierres M (1986) Accessory molecules and T cell activation. I. Antigen receptor avidity differentially influences T cell sensitivity to inhibition by monoclonal antibodies to LFA-1 and L3T4. Eur J Immunol 16:1385–1390
Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P (2001) Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2:361–367
Richardson C, Jasin M (2000) Coupled homologous and nonhomologous repair of a double-strand break preserves genomic integrity in mammalian cells. Mol Cell Biol 20:9068–9075
Rock EP, Sibbald PR, Davis MM, Chien YH (1994) CDR3 length in antigen-specific immune receptors. J Exp Med 179:323–328
Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146:905–916
Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low X-ray doses. Proc Natl Acad Sci 100:5057–5062
Ruemmele FM, Russo P, Beaulieu J, Dionne S, Levy E, Lentze MJ, Seidman EG (1999) Susceptibility to FAS-induced apoptosis in human nontumoral enterocytes: role of costimulatory factors. J Cell Physiol 181:45–54
Saintigny Y, Delacote F, Vares G, Petitot F, Lambert S, Averbeck D, Lopez BS (2001) Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J 20:3861–3870
Schild H, Mavaddat N, Litzenberger C, Ehrich EW, Davis MM, Bluestone JA, Matis L, Draper RK, Chien YH (1994) The nature of major histocompatibility complex recognition by gamma delta T cells. Cell 76:29–37
Sharp LL, Jameson JM, Cauvi G, Havran WL (2005) Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immunol 6:73–79
Shi L, Mai S, Israels S, Browne K, Trapani JA, Greenberg AH (1997) Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J Exp Med 185:855–866
Steege JC, Buurman WA, Forget PP (1997) The neonatal development of intraepithelial and lamina propria lymphocytes in the murine small intestine. Dev Immunol 5:121–128
Strater J, Wellisch I, Riedl S, Walczak H, Koretz K, Tandara A, Krammer PH, Moller P (1997) CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology 113:160–167
Sugahara S, Shimizu T, Yoshida Y, Aiba T, Yamagiwa S, Asakura H, Abo T (1999) Extrathymic derivation of gut lymphocytes in parabiotic mice. Immunology 96:57–65
Suzuki S, Sugahara S, Shimizu T, Tada T, Minagawa M, Maruyama S, Watanabe H, Saito H, Ishikawa H, Hatakeyama K, Abo T (1998) Low level of mixing of partner cells seen in extrathymic T cells in the liver and intestine of parabiotic mice: its biological implication. Eur J Immunol 28:3719–3729
Suzuki H, Jeong KI, Okutani T, Doi K (2000) Regional variations in the number and subsets of intraepithelial lymphocytes in the mouse small intestine. Comp Med 50:39–42
Sydora BC, Mixter PF, Houlden B, Hershberg R, Levy R, Comay M, Bluestone J, Kronenberg M (1993) T-cell receptor gamma delta diversity and specificity of intestinal intraepithelial lymphocytes: analysis of IEL-derived hybridomas. Cell Immunol 152:305–322
Tamura A, Soga H, Yaguchi K, Yamagishi M, Toyota T, Sato J, Oka Y, Itoh T (2003) Distribution of two types of lymphocytes (intraepithelial and lamina-propria-associated) in the murine small intestine. Cell Tissue Res 313:47–53
Tang X, Hui ZG, Cui XL, Garg R, Kastan MB, Xu B (2008) A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage. Mol Cell Biol 28:2559–2566
Targan SR, Deem RL, Liu M, Wang S, Nel A (1995) Definition of a lamina propria T cell responsive state. Enhanced cytokine responsiveness of T cells stimulated through the CD2 pathway. J Immunol 154:664–675
Trapani JA (2012) Granzymes, cytotoxic granules and cell death: the early work of Dr. Jurg Tschopp. Cell Death Differ 19:21–27
Trapani JA, Davis J, Sutton VR, Smyth MJ (2000) Proapoptotic functions of cytotoxic lymphocyte granule constituents in vitro and in vivo. Curr Opin Immunol 12:323–329
Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H, Tsujikawa K, Yamamoto H (2003) Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol 171:5507–5513
Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, Sato S, Tsujimura T, Yamamoto M, Yokota Y, Kiyono H, Miyasaka M, Ishii KJ, Akira S (2008) Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 9:769–776
Urboniene D, Babusyte A, Lotvall J, Sakalauskas R, Sitkauskiene B (2013) Distribution of gammadelta and other T-lymphocyte subsets in patients with chronic obstructive pulmonary disease and asthma. Respir Med 107:413–423
Vroom TM, Scholte G, Ossendorp F, Borst J (1991) Tissue distribution of human gamma delta T cells: no evidence for general epithelial tropism. J Clin Pathol 44:1012–1017
Wei S, Gamero AM, Liu JH, Daulton AA, Valkov NI, Trapani JA, Larner AC, Weber MJ, Djeu JY (1998) Control of lytic function by mitogen-activated protein kinase/extracellular regulatory kinase 2 (ERK2) in a human natural killer cell line: identification of perforin and granzyme B mobilization by functional ERK2. J Exp Med 187:1753–1765
Weintraub BC, Jackson MR, Hedrick SM (1994) Gamma delta T cells can recognize nonclassical MHC in the absence of conventional antigenic peptides. J Immunol 153:3051–3058
Yaguchi K, Kayaba S, Soga H, Yamagishi M, Tamura A, Kasahara S, Ohara S, Satoh J, Oka Y, Toyota T, Itoh T (2004) DNA fragmentation and detachment of enterocytes induced by anti-CD3 mAb-activated intraepithelial lymphocytes. Cell Tissue Res 315:71–84
Yu Q, Tang C, Xun S, Yajima T, Takeda K, Yoshikai Y (2006) MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes. J Immunol 176:6180–6185
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This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (20590181 to MO, and 21590207 and 15K08146 to TI) and the Japan Science and Technology Agency (JST).
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Ogata, M., Itoh, T. Gamma/delta intraepithelial lymphocytes in the mouse small intestine. Anat Sci Int 91, 301–312 (2016). https://doi.org/10.1007/s12565-016-0341-2
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DOI: https://doi.org/10.1007/s12565-016-0341-2