Yin-yang Regulation Of Humoral Immunity By CD4~+ T Cells

The production of neutralizing antibodies is required for the development of protective immunity to most infectious diseases. The importance of antibody production is exemplified not only by their ability to establish serological memory that provides long-lasting protection against pathogen infection, but also by the success of most vaccines, which rely on antibody responses for their efficacy. The differentiation of B cells to antibody-secreting cells is dependent on GC reaction, which is regulated by the instructive signals raised from T_FH cells and T_FR cells. In this process, T_FH cells provide helper signals to B cells, positively promote GC formation, whereas T_FR cells function as negative regulators of GC responses. Both T_FH and T_FR cells are working together to maintain the balance between immune activation and tolerance. Thus, investigating the differentiation and function of T_FH and T_FR cells is very important in improving protective immunity or treating autoimmune diseases.1. TCF-1 regulates T_FH differentiation during acute viral infection.T_FH cell differentiation is a multistage, multifactorial process. The fate commitment of the T_FH subset is initiated as early as 2 days after dendritic cell priming, in the regulation of master transcription factor Bcl6. With regard to regulation of T_FH cells, Cytokine-STAT, Batf, c-Maf, IRF-4, Ascl2 have been reported to be the positive regulator of T_FH cells. By contrast, Blimp1（encoded by Prdm1） inhibits T_FH differentiation by antagonizing Bcl6. Despite these advances, whether and how other factors are involved in the regulation of Bcl6 expression for the adoption of the T_FH fate by activated CD4 T cells remains unclear.The Wnt pathway effector, TCF-1, encoded by Tcf7 was induced during early T cell lineage commitment process and has been known to be critical for T cell production. TCF-1 is also important in the regulation of the immune responses, including promoting TH2 differentiation and the formation of memory CD8 T cells. In this study, we found upon acute viral infection, TCF-1 is most abundantly expressed by T_FH cells and localizes to the nuclei of those cells. We determined that TCF-1 deficiency in CD4 T cells severely impairs T_FH differentiation and the effector function that assists B cell responses. TCF-1 directly binds to the Bcl6 promoter and Prdm1 5’-regulatory regions, activating Bcl6 but repressing Blimp1 expression. In addition, TCF-1 forms a complex with Bcl6 and increases Bcl6 transcription. Notably, TCF-1 regulates early T_FH priming and is required for T_FH function in the late-stage T_FH differentiation.2. The kinase mTORC1 regulates the generation and suppressive function of follicular regulatory T cellsT_FR differentiation is a multi-step and multifactor process orchestrated by various immune signals in both the T-cell zone and B-cell follicles. The regulators of T_FR cell differentiation including Bcl6, NFAT2, TRAF3, Id2/Id3, TCR and PD1.Currently, the mechanisms by which these immune signals dictate the fate of functional T_FR cells remains poorly understood.The mechanistic target of Rapamycin（mTOR） is an evolutionarily conserved serine/threonine kinase that controls various cellular processes, including cell growth, proliferation and survival, by sensing and integrating environmental cues. Here, we examined the role of mTOR signaling in the regulation of T_FR-cell differentiation and effector function. In response to protein immunization or acute viral infection, T_FR cells exhibited an increase in mTORC1 signaling activity compared with Treg and T_FH cells. The deletion of the mTORC1 component Raptor, but not the mTORC2 component Rictor in Treg cells inhibited the differentiation of Treg cells into T_FR cells. Furthermore, the deletion or attenuation of mTORC1 signaling in differentiated T_FR cells severely inhibited the T_FR-cell inhibitory functions associated with T_FH- and GC B-cell responses. Mechanistically, the depletion of mTORC1 in T_FR precursors disrupted the phosphorylation of signal transducer and activator transcription 3（p-STAT3）, resulting in a reduced expression of transcription factor T-cell factor 1（TCF-1）. TCF-1 induced the expression of transcription factor Bcl-6 and promoted T_FR differentiation. Together, these findings demonstrate that mTORC1 signaling plays a critical role in the maintenance of humoral immune homeostasis by promoting T_FR-cell differentiation and suppressor function.