Graduate Group in Microbiology, University of California, Davis, Davis, California, USA.
J Virol. 2012 Jul;86(13):7146-57. doi: 10.1128/JVI.06904-11. Epub 2012 Apr 24.
Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (T(FH)) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of T(FH) subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (T(GC)) as lymph node-resident CD4(+) ICOS(+) CXCR4(+) CXCR5(+) PSGL-1(lo) PD-1(hi) cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only T(FH) subsets missing in influenza virus-infected, germinal center-deficient SAP(-/-) mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as "extrafollicular" helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS(+) subsets induced similar antibody levels in vitro, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T(FH) function.
流感病毒感染导致强烈的、主要依赖 T 细胞的滤泡外和生发中心 B 细胞反应，为针对同源病毒株提供终生的体液免疫。滤泡辅助性 T 细胞（T(FH)）是体液免疫的关键调节者。关于调节早期滤泡外和晚期生发中心 B 细胞反应的 T(FH)亚群的存在、特性和功能仍存在疑问。本研究表明，ICOS 而非 CXCR5 标记由流感病毒感染诱导的具有 B 辅助活性的 T 细胞，并确定生发中心 T 细胞（T(GC)）为淋巴结驻留的 CD4(+)ICOS(+)CXCR4(+)CXCR5(+)PSGL-1(lo)PD-1(hi)细胞。CXCR4 表达强度进一步区分了它们在生发中心的亮区和暗区位置。该群体在区域淋巴结中强烈出现，并且动力学与生发中心 B 细胞相似，并且是在流感病毒感染、生发中心缺陷 SAP(-/-)小鼠中缺失的唯一 T(FH)亚群，之前的研究表明，这些小鼠在二次流感病毒挑战后缺乏保护性记忆反应，因此表明 CXCR4 和 CXCR5 共表达的 CD4 辅助细胞在抗病毒 B 细胞免疫中具有非冗余功能。在 B 细胞介导的自身免疫中存在的 CXCR4-单阳性 T 细胞，被认为是“滤泡外”辅助 T 细胞，尽管存在明显的滤泡外 B 细胞反应，但在整个反应过程中都很少见，这揭示了自身免疫和感染诱导的 T 依赖性 B 细胞反应之间的根本差异。虽然所有 ICOS(+)亚群在体外诱导相似的抗体水平，但 CXCR5-单阳性 T 细胞在诱导 B 细胞增殖方面更具优势。T 细胞定位的调节，由 CXCR4 和 CXCR5 的单阳性和共表达标记，可能是 T(FH)功能的重要决定因素。
