• 1
    Sacks, D. and Noben-Trauth, N., The immunology of susceptibility and resistance to Leishmania major in mice. Nat. Rev. Immunol. 2002. 2: 845858.
  • 2
    Couper, K. N., Blount, D. G., Wilson, M. S., Hafalla, J. C., Belkaid, Y., Kamanaka, M., Flavell, R. A. et al., IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog. 2008. 4: e1000004.
  • 3
    Belkaid, Y., Blank, R. B. and Suffia, I., Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunol. Rev. 2006. 212: 287300.
  • 4
    Colpitts, S. L. and Scott, P., The early generation of a heterogeneous CD4+ T cell response to Leishmania major. J. Immunol. 2010. 185: 24162423.
  • 5
    Hataye, J., Moon, J. J., Khoruts, A., Reilly, C. and Jenkins, M. K., Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 2006. 312: 114116.
  • 6
    Badovinac, V. P., Haring, J. S. and Harty, J. T., Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection. Immunity 2007. 26: 827841.
  • 7
    Stetson, D. B., Mohrs, M., Mallet-Designe, V., Teyton, L. and Locksley, R. M., Rapid expansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo. Immunity 2002. 17: 191200.
  • 8
    Bertholet, S., Debrabant, A., Afrin, F., Caler, E., Mendez, S., Tabbara, K. S., Belkaid, Y. and Sacks, D. L., Antigen requirements for efficient priming of CD8+ T cells by Leishmania major-infected dendritic cells. Infect Immun. 2005. 73: 66206628.
  • 9
    Rudensky, A., Rath, S., Preston-Hurlburt, P., Murphy, D. B. and Janeway, C. A., Jr., On the complexity of self. Nature 1991. 353: 660662.
  • 10
    Shimonkevitz, R., Colon, S., Kappler, J. W., Marrack, P. and Grey, H. M., Antigen recognition by H-2-restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J. Immunol. 1984. 133: 20672074.
  • 11
    Moon, J. J., Chu, H. H, Pepper, M., McSorley, S. J., Jameson, S. C., Kedl, R. M. and Jenkins, M. K., Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 2007. 27: 203213.
  • 12
    DeKruyff, R. H., Fang, Y. and Umetsu, D. T., Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J. Immunol. 1998. 160: 22312237.
  • 13
    Belkaid, Y., Hoffmann, K. F., Mendez, S., Kamhawi, S., Udey, M. C., Wynn, T. A. and Sacks, D. L., The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 2001. 194: 14971506.
  • 14
    Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. and Sacks, D. L., CD4+CD25 +regulatory T cells control Leishmania major persistence and immunity. Nature 2002. 420: 502507.
  • 15
    Suffia, I. J., Reckling, S. K., Piccirillo, C. A., Goldszmid, R. S. and Belkaid, Y., Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 2006. 203: 777788.
  • 16
    Pepper, M., Linehan, J. L., Pagan, A. J., Zell, T., Dileepan, T., Cleary, P. P. and Jenkins, M. K., Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat. Immunol. 2010. 11: 8389.
  • 17
    Moon, J. J., Dash, P., Oguin, T. H., 3rd, McClaren, J. L., Chu, H. H., Thomas, P. G. and Jenkins, M. K., Quantitative impact of thymic selection on Foxp3+ and Foxp3- subsets of self-peptide/MHC class II-specific CD4+ T cells. Proc. Natl. Acad. Sci. USA 2011. 108: 1460214607.
  • 18
    Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y. and Shevach, E. M., Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 2010. 184: 34333441.
  • 19
    Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G. and Glimcher, L. H., A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000. 100: 655669.
  • 20
    Hori, S., Nomura, T. and Sakaguchi, S., Control of regulatory T cell development by the transcription factor Foxp3. Science 2003. 299: 10571061.
  • 21
    Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y., Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 2003. 4: 330336.
  • 22
    Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B. and Campbell, D. J., The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 2009. 10: 595602.
  • 23
    Anderson, C. F., Oukka, M., Kuchroo, V. J. and Sacks, D., CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 2007. 204: 285297.
  • 24
    McLachlan, J. B., Catron, D. M., Moon, J. J. and Jenkins, M. K., Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. Immunity 2009. 30: 277288.
  • 25
    Jin, H. T., Anderson, A. C., Tan, W. G., West, E. E., Ha, S. J., Araki, K., Freeman, G. J., Kuchroo, V. K. and Ahmed, R., Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 2010. 107: 1473314738.
  • 26
    Madan, R., Demircik, F., Surianarayanan, S., Allen, J. L., Divanovic, S., Trompette, A., Yogev, N. et al., Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J. Immunol. 2009. 183: 23122320.
  • 27
    Homann, D., Teyton, L. and Oldstone, M. B., Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat. Med. 2001. 7: 913919.
  • 28
    Pepper, M., Pagan, A. J., Igyarto, B. Z., Taylor, J. J. and Jenkins, M. K., Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 2011. 35: 583595.
  • 29
    Wolf, A. J., Desvignes, L., Linas, B., Banaiee, N., Tamura, T., Takatsu, K. and Ernst, J. D., Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J. Exp. Med. 2008. 205: 105115.
  • 30
    Stager, S., Maroof, A., Zubairi, S., Sanos, S. L., Kopf, M. and Kaye, P. M., Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells. Eur. J. Immunol. 2006. 36: 17641771.
  • 31
    Reiley, W. W., Shafiani, S., Wittmer, S. T., Tucker-Heard, G., Moon, J. J., Jenkins, M. K., Urdahl, K. B. et al., Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. USA 2010. 107: 1940819413.
  • 32
    Vezys, V., Masopust, D., Kemball, C. C., Barber, D. L., O'Mara, L. A., Larsen, C. P., Pearson, T. C. et al., Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 2006. 203: 22632269.
  • 33
    Gray, P. M., Reiner, S. L., Smith, D. F., Kaye, P. M. and Scott, P., Antigen-experienced T cells limit the priming of naive T cells during infection with Leishmania major. J. Immunol. 2006. 177: 925933.
  • 34
    Obst, R., van Santen, H. M., Mathis, D. and Benoist, C., Antigen persistence is required throughout the expansion phase of a CD4(+) T cell response. J. Exp. Med. 2005. 201: 15551565.
  • 35
    Yarke, C. A., Dalheimer, S. L., Zhang, N., Catron, D. M., Jenkins, M. K. and Mueller, D. L., Proliferating CD4+ T cells undergo immediate growth arrest upon cessation of TCR signaling in vivo. J. Immunol. 2008. 180: 156162.
  • 36
    Lee, S. J., McLachlan, J. B., Kurtz, J. R., Fan, D., Winter, S. E., Baumler, A. J., Jenkins, M. K. et al., Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog. 2012. 8: e1002499.
  • 37
    Heinzel, F. P., Sadick, M. D., Holaday, B. J., Coffman, R. L. and Locksley, R. M., Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 1989. 169: 5972.
  • 38
    Jankovic, D., Kullberg, M. C., Feng, C. G., Goldszmid, R. S., Collazo, C. M., Wilson, M., Wynn, T. A. et al., Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 2007. 204: 273283.
  • 39
    Freitas do Rosario, A. P., Lamb, T., Spence, P., Stephens, R., Lang, A., Roers, A., Muller, W. et al., IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 2012. 188: 11781190.
  • 40
    Darrah, P. A., Patel, D. T., De Luca, P. M., Lindsay, R. W., Davey, D. F., Flynn, B. J., Hoff, S. T. et al., Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat. Med. 2007. 13: 843850.
  • 41
    Wherry, E. J., T cell exhaustion. Nat. Immunol. 2011. 12: 492499.
  • 42
    Bustamante, J. M., Bixby, L. M. and Tarleton, R. L., Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nat. Med. 2008. 14: 542550.
  • 43
    Da-Cruz, A. M., Oliveira-Neto, M. P., Bertho, A. L., Mendes-Aguiar, C. O. and Coutinho, S. G., T cells specific to leishmania and other nonrelated microbial antigens can migrate to human leishmaniasis skin lesions. J. Invest. Dermatol. 130: 13291336.
  • 44
    Saraiva, M., Christensen, J. R., Veldhoen, M., Murphy, T. L., Murphy, K. M. and O'Garra, A., Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 2009. 31: 209219.
  • 45
    Stumhofer, J. S., Silver, J. S., Laurence, A., Porrett, P. M., Harris, T. H., Turka, L. A., Ernst, M. et al., Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 2007. 8: 13631371.
  • 46
    Awasthi, A., Carrier, Y., Peron, J. P., Bettelli, E., Kamanaka, M., Flavell, R. A., Kuchroo et al., A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 2007. 8: 13801389.
  • 47
    Pot, C., Jin, H., Awasthi, A., Liu, S. M., Lai, C. Y., Madan, R., Sharpe, A. H. et al., Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 2009. 183: 797801.
  • 48
    Apetoh, L., Quintana, F. J., Pot, C., Joller, N., Xiao, S., Kumar, D., Burns, E. J. et al., The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 2010. 11: 854861.
  • 49
    Anderson, C. F., Stumhofer, J. S., Hunter, C. A. and Sacks, D., IL-27 regulates IL-10 and IL-17 from CD4+ cells in nonhealing Leishmania major infection. J. Immunol. 2009. 183: 46194627.
  • 50
    Debrabant, A., Gottlieb, M. and Dwyer, D. M., Isolation and characterization of the gene encoding the surface membrane 3′-nucleotidase/nuclease of Leishmania donovani. Mol. Biochem. Parasitol. 1995. 71: 5163.
  • 51
    Rees, W., Bender, J., Teague, T. K., Kedl, R. M., Crawford, F., Marrack, P. and Kappler, J., An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc. Natl. Acad. Sci. USA 1999. 96: 97819786.
  • 52
    Debrabant, A., Ghedin, E. and Dwyer, D. M., Dissection of the functional domains of the Leishmania surface membrane 3′-nucleotidase/nuclease, a unique member of the class I nuclease family. J. Biol. Chem. 2000. 275: 1636616372.
  • 53
    Spath, G. F. and Beverley, S. M., A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation. Exp. Parasitol. 2001. 99: 97103.
  • 54
    Peters, N. C., Kimblin, N., Secundino, N., Kamhawi, S., Lawyer, P. and Sacks, D. L., Vector transmission of leishmania abrogates vaccine-induced protective immunity. PLoS Pathog. 2009. 5: e1000484.
  • 55
    Moon, J. J., Chu, H. H., Hataye, J., Pagan, A. J., Pepper, M., McLachlan, J. B., Zell, T. and Jenkins, M. K., Tracking epitope-specific T cells. Nat. Protoc. 2009. 4: 565581.
  • 56
    Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. and Jenkins, M. K., Visualizing the generation of memory CD4 T cells in the whole body. Nature 2001. 410: 101105.