Hu Zhuting, Blackman Marcia A, Kaye Kenneth M, Usherwood Edward J
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756;
Trudeau Institute, Saranac Lake, NY 12983; and.
J Immunol. 2015 Mar 15;194(6):2746-56. doi: 10.4049/jimmunol.1401928. Epub 2015 Feb 6.
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.
CD4(+) T细胞对于控制病毒感染、T细胞记忆及免疫监视至关重要。我们使用gp150特异性TCR转基因小鼠研究了鼠γ-疱疹病毒68（MHV-68）特异性CD4(+) T细胞的分化和功能。相较于此前针对该病毒的可用方法，这使得对CD4(+) T细胞应答特征的研究更为详尽。大多数gp150特异性CD4(+) T细胞表达T-bet并产生IFN-γ，表明MHV-68感染在很大程度上促使CD4(+) T细胞分化为Th1亚群，而一些则成为滤泡辅助性T细胞和Foxp3(+)调节性T细胞。在缺乏CD8(+) T细胞和B细胞的情况下，这些CD4(+) T细胞对MHV-68感染具有保护作用，且保护作用依赖于IFN-γ的分泌。基于淋巴细胞Ag 6C（Ly6C）的表达，在CD4(+) T细胞中观察到明显的异质性。Ly6C表达与IFN-γ、TNF-α和颗粒酶B的产生；T-bet和KLRG1的表达；增殖；以及CD4(+) T细胞介导的细胞毒性呈正相关。Ly6C表达与存活率、CCR7表达及二次扩增潜能呈负相关。在体内再次接触抗原后，Ly6C(+)和Ly6C(-) gp150特异性CD4(+) T细胞能够双向相互转化。这些结果表明，Ly6C表达与效应性CD4(+) T细胞的抗病毒活性密切相关，但与记忆潜能呈负相关。Ly6C(+)和Ly6C(-)细胞之间的相互转化可能在MHV-68感染期间维持两个抗原特异性CD4(+) T细胞群体之间的平衡。这些发现对于Ly6C作为在持续性病毒感染期间区分功能不同的CD4(+) T细胞的表面标志物具有重要意义。
