Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection
Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection
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DOI：
10.1128/jvi.06904-11
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Baumgarth, Nicole
中科院分区：
文献类型：
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作者：
Elsner, Rebecca A.;Ernst, David N.;Baumgarth, Nicole
流感病毒感染导致强烈的、主要依赖于T细胞的滤泡外和生发中心B细胞反应，从而提供针对同型病毒株的终生体液免疫。滤泡辅助 T 细胞 (T-FH) 是体液免疫的关键调节因子。关于调节早期滤泡外和后来生发中心 B 细胞反应的 T-FH 亚群的存在、身份和功能仍然存在疑问。这项研究表明，ICOS 而不是 CXCR5 标记了由流感病毒感染诱导的具有 B 辅助活性的 T 细胞，并将生发中心 T 细胞 (T-GC) 鉴定为淋巴结驻留 CD4(+) ICOS+ CXCR4(+) CXCR5(+) PSGL-1(lo) PD-I-hi 细胞。 CXCR4表达强度进一步区分了它们的生发中心亮区和暗区位置。该群体在区域淋巴结中强烈出现，其动力学与生发中心 B 细胞相似，是流感病毒感染、生发中心缺陷 SAP(-/-) 小鼠中唯一缺失的 T 亚群，这些小鼠先前显示在继发性流感病毒攻击后缺乏保护性记忆反应，从而表明 CXCR4 和 CXCR5 共表达 CD4 辅助细胞在抗病毒 B 细胞免疫中的非冗余功能。尽管滤泡外 B 细胞反应显着，但存在于 B 细胞介导的自身免疫中并被视为“滤泡外”辅助 T 细胞的 CXCR4 单阳性 T 细胞在整个反应过程中很少见，这揭示了自身免疫和感染诱导的 T 依赖性 B 细胞反应的根本差异。虽然所有 ICOS+ 亚群在体外诱导的抗体水平相似，但 CXCR5 单阳性 T 细胞在诱导 B 细胞增殖方面更胜一筹。以 CXCR4 和 CXCR5 的单表达和共表达为标志的 T 细胞定位调节可能是 T-FH 功能的重要决定因素。
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-I-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 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.