Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.
J Exp Med. 2011 Jul 4;208(7):1377-88. doi: 10.1084/jem.20102065. Epub 2011 Jun 27.
T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell-expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6(+) T cells appear at the T-B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6(+) PD-1(hi) T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6(+) T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.
滤泡辅助 T 细胞（Tfh 细胞）定位于滤泡中，在那里为突变的生发中心（GC）B 细胞提供生长和选择信号，从而促进其分化为高亲和力的长寿浆细胞和记忆 B 细胞。T 细胞依赖的 B 细胞分化也发生在滤泡外，产生未突变的浆细胞，这对于早期抵御微生物感染非常重要。已经表明 T 细胞中的 Bcl-6 表达对于 Tfh 细胞和 GC B 细胞的形成是必不可少的，但对于其在生理滤泡外抗体反应中的要求知之甚少。我们使用了几种可以明确区分生发中心起源和滤泡外浆细胞的小鼠模型，结合抗原特异性 T 和 B 细胞，表明 T 细胞表达的 Bcl-6 缺失显著减少了 T 细胞依赖的滤泡外抗体反应。Bcl-6(+)T 细胞在 T 细胞初始后不久出现在 T-B 边界，并且在 GC 形成之前出现，并且这些细胞表达低水平的 PD-1。它们的出现早于 GC 内发现的 Bcl-6(+)PD-1(hi)T 细胞。IL-21 早期作用于促进滤泡内和滤泡外抗体反应。总之，Bcl-6(+)T 细胞在 B 细胞初始时对于形成滤泡外抗体反应是必需的，并且这些前 GC Tfh 细胞可以在表型上与 GC Tfh 细胞区分开来。
