Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells.

Abstract

Lineage commitment and differentiation into CD4⁺ T cell subsets reflect an interplay between chromatin regulators and transcription factors (TF). Follicular T cell development is regulated by the Bcl6 TF, which helps determine the phenotype and follicular localization of both CD4⁺ follicular helper T cells (T_FH) and follicular regulatory T cells (T_FR). Here we show that Bcl6-dependent control of follicular T cells is mediated by a complex formed between Bcl6 and the Mi-2β-nucleosome-remodeling deacetylase complex (Mi-2β-NuRD). Formation of this complex reflects the contribution of the intracellular isoform of osteopontin (OPN-i), which acts as a scaffold to stabilize binding between Bcl6 and the NuRD complex that together regulate the genetic program of both T_FH and T_FR cells. Defective assembly of the Bcl6-NuRD complex distorts follicular T cell differentiation, resulting in impaired T_FR development and skewing of the T_FH lineage toward a T_H1-like program that includes expression of Blimp1, Tbet, granzyme B, and IFNγ. These findings define a core Bcl6-directed transcriptional complex that enables CD4⁺ follicular T cells to regulate the germinal center response.