Helmold Hait Sabrina, Hogge Christopher James, Rahman Mohammad Arif, Hunegnaw Ruth, Mushtaq Zuena, Hoang Tanya, Robert-Guroff Marjorie
Immune Biology of Retroviral Infection Section, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2021 Jan 28;11:608003. doi: 10.3389/fimmu.2020.608003. eCollection 2020.
T follicular helper (T) cells are pivotal in lymph node (LN) germinal center (GC) B cell affinity maturation. Circulating CXCR5 CD4 T (cT) cells have supported memory B cell activation and broadly neutralizing antibodies in HIV controllers. We investigated the contribution of LN SIV-specific T and cT cells to Env-specific humoral immunity in female rhesus macaques following a mucosal Ad5hr-SIV recombinant priming and SIV gp120 intramuscular boosting vaccine regimen and following SIV vaginal challenge. T and B cells were characterized by flow cytometry. B cell help was evaluated in T-B cell co-cultures and by real-time PCR. Vaccination induced Env-specific T and Env-specific memory (ESM) B cells in LNs. LN Env-specific T cells post-priming and GC ESM B cells post-boosting correlated with rectal Env-specific IgA titers, and GC B cells at the same timepoints correlated with vaginal Env-specific IgG titers. Vaccination expanded cT cell responses, including CD25 Env-specific cT cells that correlated negatively with vaginal Env-specific IgG titers but positively with rectal Env-specific IgA titers. Although cT cells post-2 boost positively correlated with viral-loads following SIV challenge, cT cells of SIV-infected and protected macaques supported maturation of circulating B cells into plasma cells and IgA release in co-culture. Additionally, cT cells of naïve macaques promoted upregulation of genes associated with B cell proliferation, BCR engagement, plasma cell maturation, and antibody production, highlighting the role of cT cells in blood B cell maturation. Vaccine-induced LN T and GC B cells supported anti-viral mucosal immunity while cT cells provided B cell help in the periphery during immunization and after SIV challenge. Induction of T responses in blood and secondary lymphoid organs is likely desirable for protective efficacy of HIV vaccines.
滤泡辅助性T（TFH）细胞在淋巴结（LN）生发中心（GC）B细胞亲和力成熟过程中起关键作用。循环中的CXCR5 CD4 T（cT）细胞在HIV控制者体内支持记忆B细胞活化及广泛中和抗体的产生。我们研究了在黏膜Ad5hr - SIV重组疫苗初免和SIV gp120肌肉注射加强免疫疫苗方案后以及SIV阴道攻击后，LN中SIV特异性T细胞和cT细胞对恒河猴雌性Env特异性体液免疫的贡献。通过流式细胞术对T细胞和B细胞进行表征。在T - B细胞共培养物中并通过实时PCR评估B细胞辅助作用。疫苗接种诱导了LN中Env特异性T细胞和Env特异性记忆（ESM）B细胞。初免后LN中的Env特异性T细胞和加强免疫后GC中的ESM B细胞与直肠Env特异性IgA滴度相关，而同一时间点的GC B细胞与阴道Env特异性IgG滴度相关。疫苗接种扩大了cT细胞反应，包括CD25 Env特异性cT细胞，其与阴道Env特异性IgG滴度呈负相关，但与直肠Env特异性IgA滴度呈正相关。尽管两次加强免疫后的cT细胞与SIV攻击后的病毒载量呈正相关，但SIV感染且得到保护的猕猴的cT细胞在共培养中支持循环B细胞成熟为浆细胞并释放IgA。此外，未感染猕猴的cT细胞促进了与B细胞增殖、BCR结合、浆细胞成熟和抗体产生相关基因的上调，突出了cT细胞在血液B细胞成熟中的作用。疫苗诱导的LN T细胞和GC B细胞支持抗病毒黏膜免疫，而cT细胞在免疫期间及SIV攻击后在外周提供B细胞辅助作用。在血液和二级淋巴器官中诱导T细胞反应可能对HIV疫苗的保护效果是必要的。
