T cell-dependent antibody responses constitute essential protection against pathogens. Follicular helper T (TFH) cells provide critical help to B cells for effective production of high-affinity antibodies by germinal center (GC) B cells, generation of long-lived plasma cells and memory B cells. The TFH-B cell cooperativity underlies immunological memory induced by vaccines and pathogenesis of autoimmune disorders. Understanding how TFH cells develop and function is a prerequisite for formulating new, more efficacious vaccines. Ezh2 has histone methyltransferase (HMT) activity and is the sole enzymatic component in Polycomb repressive complex 2 that deploys the H3K27me3 repressive histone mark for gene repression. Ezh2 critically regulates cytokine production and lineage stability of T helper 1, 2, and regulatory T cells but has not been studies in TFH cells. Using an in vivo viral infection model, our preliminary studies showed that Ezh2 was progressively induced in TFH cells and genetic ablation of Ezh2 impaired TFH differentiation. Ezh2 expression was also elevated in pathogenic TFH cells in an SLE mouse model. We hypothesize that Ezh2 uses multipronged mechanisms to promote TFH differentiation and memory TFH formation.
Our specific aims are:
Specific Aim 1. To elucidate the genetic program controlled by Ezh2 in promoting TFH differentiation.
Specific Aim 2. To dissect the requirements for Ezh2 in regulation of TFH cell epigenome and TFH gene accessibility. Collectively, these in vivo infection and protein immunization models will allow us to define the functional requirements for Ezh2 in TFH differentiation at both effector and memory phases. Systematic genetic dissection will determine ?what? Ezh2 target genes are in the TFH program and further delineate ?how? Ezh2 regulates its downstream targets, thus providing mechanistic insights into generation of protective effector and memory TFH cells. Because over-exuberant TFH cell activity and excessive antibody production underlie pathogenesis of several autoimmune disorders. The proposed studies will likely yield important knowledge necessary for enhancing vaccine efficacy and for identifying new pathway(s) as therapeutic targets for treating autoimmune conditions.
Follicular helper T (TFH) cells are critical for helping B cells to produce high affinity antibodies in response to pathogen infections. This project will investigate the regulatory roles of Ezh2 in activating TFH program during acute response phase and generation of long-lasting memory TFH cells. The proposed studies will provide rationales for utilizing Ezh2 and its downstream pathways to modulate TFH and antibody responses during prime and boost vaccination.
|Li, Fengyin; Zeng, Zhouhao; Xing, Shaojun et al. (2018) Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun 9:5452|