The generation of high-affinity antibodies and avoidance of autoimmune responses after microbial infection or vaccination requires precise control of the germinal center (GC) reaction by follicular T-cell subsets. Follicular helper CD4+ T (TFH) cells induce GC formation and help GC B cells to produce protective antibody responses to invading pathogens. FoxP3+ follicular regulatory T (TFR) cells inhibit TFH-driven GC responses and prevent emergence of auto-reactive B-cells and autoantibody formation. A key element in stable differentiation of both TFH and TFR is expression of the antagonistic Bcl6?Blimp1 pair of transcription factors (TF). Our recent studies of TFH differentiation have revealed that (a) ICOS-dependent binding of OPN-i to the Bcl6-RD2 domain promotes association of Bcl6 with the Mi-2? nucleosome remodeling and histone- deacetylase complex (Mi2??NuRD) and (b) this Bcl6-containing complex is essential for efficient repression of Blimp1, TFH lineage stability and repression of alternative TH fates. We examine the molecular basis of this process in SA1. Analysis of ICOS+ TFR has also revealed an association between OPN-i, Bcl6, and components of the Mi2?-NuRD complex. We test the hypothesis that OPN-i-dependent formation of the Bcl6?Mi-2?-NuRD complex regulates a common genetic program expressed by TFR and TFH cells. This will entail identification of shared genetic loci that are co-occupied by Bcl6 and Mi2-?-NuRD according to Bio-ChIP-Seq and ?ChIP-reChIP? analyses (SA2). Finally, we define the mechanism that allows co-expression of the antagonistic Bcl6?Blimp1 transcription factors in TFR and the contribution of Blimp1 to stable development and function of TFR cells is addressed in SA3. These studies should provide new insight into the molecular control of TFH/TFR differentiation and establish a foothold for new therapeutic approaches to autoimmune disease.
The generation of high-affinity antibodies and avoidance of autoimmune responses after microbial infection or vaccination requires precise control of the germinal center reaction by follicular T-cell subsets: follicular helper cells (TFH) and follicular regulatory cells (TFR). The proposed studies will help define the molecular and genetic mechanisms that control differentiation of this critical pair of follicular T-cells. This approach should allow new therapeutic strategies based on targeting the genetic and epigenetic elements that regulate TFH or TFR cells development in the context of autoimmune disease or vaccination again microbial pathogens.
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