title: Functional heterogeneity in the CD4+ T cell response to murine γ-herpesvirus 68.
abstract: CD4(+) T cells are critical for the control of virus infections, T cell memory, and immune surveillance. We studied the differentiation and function of murine γ-herpesvirus 68 (MHV-68)-specific CD4(+) T cells using gp150-specific TCR-transgenic mice. This allowed a more detailed study of the characteristics of the CD4(+) T cell response than did previously available approaches for this virus. Most gp150-specific CD4(+) T cells expressed T-bet and produced IFN-γ, indicating that MHV-68 infection triggered differentiation of CD4(+) T cells largely into the Th1 subset, whereas some became follicular Th cells and Foxp3(+) regulatory T cells. These CD4(+) T cells were protective against MHV-68 infection in the absence of CD8(+) T cells and B cells, and protection depended on IFN-γ secretion. Marked heterogeneity was observed in the CD4(+) T cells, based on lymphocyte Ag 6C (Ly6C) expression. Ly6C expression positively correlated with IFN-γ, TNF-α, and granzyme B production; T-bet and KLRG1 expression; proliferation; and CD4(+) T cell-mediated cytotoxicity. Ly6C expression inversely correlated with survival, CCR7 expression, and secondary expansion potential. Ly6C(+) and Ly6C(-) gp150-specific CD4(+) T cells were able to interconvert in a bidirectional manner upon secondary Ag exposure in vivo. These results indicate that Ly6C expression is closely associated with antiviral activity in effector CD4(+) T cells but is inversely correlated with memory potential. Interconversion between Ly6C(+) and Ly6C(-) cells may maintain a balance between the two Ag-specific CD4(+) T cell populations during MHV-68 infection. These findings have significant implications for Ly6C as a surface marker to distinguish functionally distinct CD4(+) T cells during persistent virus infection.
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756;
authors: Zhuting
authors: Z
authors: Hu
authors: Trudeau Institute, Saranac Lake, NY 12983; and.
authors: Marcia A
authors: MA
authors: Blackman
authors: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Kenneth M
authors: KM
authors: Kaye
authors: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; Edward.J.Usherwood@Dartmouth.EDU.
authors: Edward J
authors: EJ
authors: Usherwood
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018144:Rhadinovirus / Q000276:immunology* / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014412:Tumor Virus Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology
chemical_list: D000950:Antigens, Ly; C494192:Ly-6C antigen, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma