Abstract
Natural T regulatory cells (NatTReg) limit immunopathology and protective immune responses induced upon microbial infection. In addition, infection increases the number and activity of NatTReg. These findings need to be conciliated with the process of ‘self–nonself’ discrimination based on the function of NatTReg committed intrathymically and positively selected (and activated) on thymic epithelial cells. A review of the available evidence comforts the assumptions that, in physiological conditions, NatTReg engaged in the immune responses to microbial infections are drawn from the autoreactive repertoire even if some may appear to be microbe specific. This contention also provides a suitable explanation for the ‘hygiene hypothesis’: infections re-enforce the physiological mechanisms of natural dominant tolerance, through the expansion of naturally occurring regulatory T cells. Accumulating evidence demonstrates that pro-inflammatory ligands of Toll-like receptors expressed by NatTReg, both of microbial (e.g., lipopolysaccharide, flagellin, peptidoglycans) and endogenous (e.g., stress proteins and degradation products of the extracellular matrix) origin, may play a critical role in their activation and expansion. As NatTReg vigorously respond to IL-2/IL-15 locally produced by ongoing effector responses, this whole set of mechanisms provides for a robust feedback process that limits tissue damage and accounts for an ‘organism-centered’ quality control of immune responses. Detailed knowledge on these molecular and cellular bases should open novel opportunities for intervention in a variety of critical conditions, such as autoimmunity, allergy, chronic infections, and cancer, for which we currently lack effective therapies.
References
Coutinho A, Caramalho I, Seixas E, Demengeot J (2005) Thymic commitment of regulatory T cells is a pathway of TCR-dependent selection that isolates repertoires undergoing positive or negative selection. Curr Top Microbiol Immunol 293:43
Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057
Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331
Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK (2005) Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 202:1375
Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115:1923
Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219
Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H (2004) Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172:6003
Mills KH, McGuirk P (2004) Antigen-specific regulatory T cells—their induction and role in infection. Semin Immunol 16:107
Morrissey PJ, Charrier K, Braddy S, Liggitt D, Watson JD (1993) CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med 178:237
Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL (1993) Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5:1461
Cahill RJ, Foltz CJ, Fox JG, Dangler CA, Powrie F, Schauer DB (1997) Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect Immun 65:3126
Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F (2005) Regulatory T cells and intestinal homeostasis. Immunol Rev 204:184
Hori S, Carvalho TL, Demengeot J (2002) CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur J Immunol 32:1282
Montagnoli C, Bacci A, Bozza S, Gaziano R, Mosci P, Sharpe AH, Romani L (2002) B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J Immunol 169:6298
Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420:502
Mittrucker HW, Kaufmann SH (2004) Mini-review: regulatory T cells and infection: suppression revisited. Eur J Immunol 34:306
Rouse BT, Suvas S (2004) Regulatory cells and infectious agents: detentes cordiale and contraire. J Immunol 173:2211
Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6:353
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151
Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033
Pinilla C, Martin R, Gran B, Appel JR, Boggiano C, Wilson DB, Houghten RA (1999) Exploring immunological specificity using synthetic peptide combinatorial libraries. Curr Opin Immunol 11:193
Wysocki CA, Jiang Q, Panoskaltsis-Mortari A, Taylor PA, McKinnon KP, Su L, Blazar BR, Serody JS (2005) Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 106:3300
D’Ambrosio D, Sinigaglia F, Adorini L (2003) Special attractions for suppressor T cells. Trends Immunol 24:122
Szanya V, Ermann J, Taylor C, Holness C, Fathman CG (2002) The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses l-selectin and high levels of CCR7. J Immunol 169:2461
Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403
Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK (2005) Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175:8051
Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116:485
Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380
Reis e Sousa C (2004) Toll-like receptors and dendritic cells: for whom the bug tolls. Semin Immunol 16:27
Beutler B, Rehli M (2002) Evolution of the TIR, tolls and TLRs: functional inferences from computational biology. Curr Top Microbiol Immunol 270:1
Kaisho T, Akira S (2004) Pleiotropic function of Toll-like receptors. Microbes Infect 6:1388
Wolf M, Schimpl A, Hunig T (2001) Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(−) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 31:1637
Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ (2002) Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196:851
Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142
Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)2 and induction of autoimmune disease by IL2 neutralization. J Exp Med 201:723
Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, Steinman RM (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigenprocessing dendritic cells. J Exp Med 198:235
Kubo T, Hatton RD, Oliver J, Liu X, Elson CO, Weaver CT (2004) Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLR-activated dendritic cells. J Immunol 173:7249
Brinster C, Shevach EM (2005) Bone marrow-derived dendritic cells reverse the anergic state of CD4+CD25+ T cells without reversing their suppressive function. J Immunol 175:7332
Modigliani Y, Pereira P, Thomas-Vaslin V, Salaun J, Burlen-Defranoux O, Coutinho A, Le Douarin N, Bandeira A (1995) Regulatory T cells in thymic epithelium-induced tolerance. I. Suppression of mature peripheral non-tolerant T cells. Eur J Immunol 25:2563
van Eden W, van der Zee R, Prakken B (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5:318
Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A (2005) Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 204:27
Modigliani Y, Bandeira A, Coutinho A (1996) A model for developmentally acquired thymus-dependent tolerance to central and peripheral antigens. Immunol Rev 149:155
Fisson S, Djelti F, Trenado A, Billiard F, Liblau R, Klatzmann D, Cohen JL, Salomon BL (2006) Therapeutic potential of self-antigen-specific CD4+ CD25+ regulatory T cells selected in vitro from a polyclonal repertoire. Eur J Immunol 36:817
Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032
Coutinho A, Gronowicz E, Bullock WW, Moller G (1974) Mechanism of hymus-independent immunocyte triggering. Mitogenic activation of B cells results in specific immune responses. J Exp Med 139:74
Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195:99
Suffia IJ, Reckling SK, Piccirillo CA, Goldszmid RS, Belkaid Y (2006) Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J Exp Med
Seddon B, Mason D (1999) Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 189:877
Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911
Otterbein LE, Soares MP, Yamashita K, Bach FH (2003) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24:449
Vitelli-Avelar DM, Sathler-Avelar R, Dias JC, Pascoal VP, Teixeira-Carvalho A, Lage PS, Eloi-Santos SM, Correa-Oliveira R, Martins-Filho OA (2005) Chagasic patients with indeterminate clinical form of the disease have high frequencies of circulating CD3+CD16−CD56+ natural killer T cells and CD4+CD25High regulatory T lymphocytes. Scand J Immunol 62:297
Lundgren A, Suri-Payer E, Enarsson K, Svennerholm AM, Lundin BS (2003) Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect Immun 71:1755
Lundgren A, Stromberg E, Sjoling A, Lindholm C, Enarsson K, Edebo A, Johnsson E, Suri-Payer E, Larsson P, Rudin A, Svennerholm AM, Lundin BS (2005) Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients. Infect Immun 73:523
Kariminia A, Bourreau E, Pascalis H, Couppie P, Sainte-Marie D, Tacchini-Cottier F, Launois P (2005) Transforming growth factor beta 1 production by CD4+ CD25+ regulatory T cells in peripheral blood mononuclear cells from healthy subjects stimulated with Leishmania guyanensis. Infect Immun 73:5908
Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, Andersen RF, Bejon P, Thompson F, Dunachie SJ, Edele F, de Souza JB, Sinden RE, Gilbert SC, Riley EM, Hill AV (2005) Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23:287
Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, Cheever AW, Sher A (2002) Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 196:505
Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170:3939
Raghavan S, Fredriksson M, Svennerholm AM, Holmgren J, Suri-Payer E (2003) Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in Helicobacter pylori-infected mice. Clin Exp Immunol 132:393
Netea MG, Sutmuller R, Hermann C, Van der Graaf CA, Van der Meer JW, van Krieken JH, Hartung T, Adema G, Kullberg BJ (2004) Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol 172:3712
Montagnoli C, Fallarino F, Gaziano R, Bozza S, Bellocchio S, Zelante T, Kurup WP, Pitzurra L, Puccetti P, Romani L (2006) Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J Immunol 176:1712
Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, Leusink M, Cheever AW, Shevach EM, Wynn TA (2004) The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol 172:3157
McKee AS, Pearce EJ (2004) CD25+CD4+ cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol 173:1224
Singh KP, Gerard HC, Hudson AP, Reddy TR, Boros DL (2005) Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology 114:410
Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y (2004) Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med 200:201
Aseffa A, Gumy A, Launois P, MacDonald HR, JA Louis, Tacchini-Cottier F (2002) The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells. J Immunol 169:3232
Liu H, Hu B, Xu D, Liew FY (2003) CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4. J Immunol 171:5012
Ji J, Masterson J, Sun J, Soong L (2005) CD4+CD25+ regulatory T cells restrain pathogenic responses during Leishmania amazonensis infection. J Immunol 174:7147
Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, Kishihara K, Tsukumo S, Yasutomo K (2004) Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 10:29
Hisaeda H, Hamano S, Mitoma-Obata C, Tetsutani K, Imai T, Waldmann H, Himeno K, Yasutomo K (2005) Resistance of regulatory T cells to glucocorticoid-viduced TNFR family-related protein (GITR) during Plasmodium yoelii infection. Eur J Immunol 35:3516
Long TT, Nakazawa S, Onizuka S, Huaman MC, Kanbara H (2003) Influence of CD4+CD25+ T cells on Plasmodium berghei NK65 infection in BALB/c mice. Int J Parasitol 33:175
Taylor MD, LeGoff L, Harris A, Malone E, Allen JE, Maizels RM (2005) Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J Immunol 174:4924
Acknowledgments
The cited experimental work produced at the IGC was supported by FCT/POCTI and FCT/POCI grants to JD and FCT fellowship to SZ and IC. We are indebted to Thiago Lopes-Carvalho and Jorge Carneiro who have certainly influenced the building of these thoughts through various discussions in the recent years.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Demengeot, J., Zelenay, S., Moraes-Fontes, M.F. et al. Regulatory T cells in microbial infection. Springer Semin Immun 28, 41–50 (2006). https://doi.org/10.1007/s00281-006-0024-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-006-0024-5