Nelson Cody S, Podestà Manuel A, Gempler Maya G, Lee Jeong-Mi, Batty Cole J, Mathenge Peterson G, Sainju Asra, Chang Matthew R, Ke Hanzhong, Chandrakar Pragya, Bechu Elsa, Richardson Sierra, Cavazzoni Cecilia B, Tullius Stefan G, Abdi Reza, Ghebremichael Musie, Haigis Marcia C, Marasco Wayne A, Sage Peter T
Transplantation Research Center, Division of Renal Medicine, Department of Medicine; and.
Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
JCI Insight. 2025 Mar 4;10(8). doi: 10.1172/jci.insight.187271. eCollection 2025 Apr 22.
Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh cell formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh cell development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming. We investigated the extent to which this rewiring of aged Tfh cells is due to the age-associated inflammatory ("inflammaging") microenvironment and found that this setting was sufficient to both block the transition of Tfh cells to a post-effector resting state and skew Tfh cells toward the age-rewired state. Together, these data suggest that aging dampens humoral immunity by cytokine-mediated rewiring of late effector Tfh cell differentiation into an activated, yet less functional, cellular state.
体液免疫由滤泡辅助性T（Tfh）细胞协调，Tfh细胞促进同源B细胞产生高亲和力的保护性抗体。在老年人中，尽管存在Tfh细胞，但接种疫苗后的体液免疫仍会减弱，这表明初始Tfh细胞形成后存在缺陷。在本研究中，我们利用小鼠和人类系统来研究衰老如何改变流感疫苗接种后Tfh细胞的分化。我们发现，年轻的Tfh细胞在流感疫苗接种后会进行渐进性分化，最终在引流淋巴结和血液中导致效应样细胞的克隆扩增。在衰老过程中，Tfh细胞发育的早期阶段正常发生。然而，衰老改变了Tfh细胞发育的后期阶段，导致了反映细胞衰老、持续促炎细胞因子产生和代谢重编程的转录程序。我们研究了衰老的Tfh细胞这种重编程在多大程度上归因于与年龄相关的炎症（“炎症衰老”）微环境，发现这种环境足以既阻止Tfh细胞向后效应静止状态的转变，又使Tfh细胞偏向于衰老重编程状态。总之，这些数据表明，衰老通过细胞因子介导的效应晚期Tfh细胞分化重编程为一种活化但功能较弱的细胞状态，从而削弱体液免疫。
