title: Tracking antigen-specific CD4+ T cells throughout the course of chronic Leishmania major infection in resistant mice.
abstract: Primary Leishmania major infection typically produces cutaneous lesions that not only heal but also harbor persistent parasites. While the opposing roles of CD4(+)  T-cell-derived IFN-γ and IL-10 in promoting parasite killing and persistence have been well established, how these responses develop from naïve precursors has not been directly monitored throughout the course of infection. We used peptide:Major Histocompatibility Complex class II (pMHCII) tetramers to investigate the endogenous, parasite-specific primary CD4(+)  T-cell response to L. major in mice resistant to infection. Maximal frequencies of IFN-γ(+)  CD4(+)  T cells were observed in the spleen and infected ears within a month after infection and were maintained into the chronic phase. In contrast, peak frequencies of IL-10(+)  CD4(+)  T cells emerged within 2 weeks of infection, persisted into the chronic phase, and accumulated in the infected ears but not the spleen, via a process that depended on local antigen presentation. T helper type-1 (Th1) cells, not Foxp3(+)  regulatory T cells, were the chief producers of IL-10 and were not exhausted. Therefore, tracking antigen-specific CD4(+)  T cells revealed that IL-10 production by Th1 cells is not due to persistent T-cell antigen receptor stimulation, but rather driven by early antigen encounter at the site of infection.
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Pagán
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Peters
authors.forename: Alain
authors.initials: A
authors.lastname: Debrabant
authors.forename: Flavia
authors.initials: F
authors.lastname: Ribeiro-Gomes
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: David L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004423:Ear; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D007371:Interferon-gamma