In Vivo Regulation of Bcl6 and T Follicular Helper Cell Development

Abstract

Follicular helper T (T_FH) cells, defined by expression of the surface markers CXCR5 and programmed death receptor-1 (PD-1) and synthesis of IL-21, require upregulation of the transcriptional repressor Bcl6 for their development and function in B cell maturation in germinal centers. We have explored the role of B cells and the cytokines IL-6 and IL-21 in the in vivo regulation of Bcl6 expression and T_FH cell development. We found that T_FH cells are characterized by a Bcl6-dependent downregulation of P-selectin glycoprotein ligand 1 (PSGL1, a CCL19- and CCL21-binding protein), indicating that, like CXCR5 and PD-1 upregulation, modulation of PSGL1 expression is part of the T_FH cell program of differentiation. B cells were neither required for initial upregulation of Bcl6 nor PSGL1 downregulation, suggesting these events preceded T–B cell interactions, although they were required for full development of the T_FH cell phenotype, including CXCR5 and PD-1 upregulation, and IL-21 synthesis. Bcl6 upregulation and T_FH cell differentiation were independent of IL-6 and IL-21, revealing that either cytokine is not absolutely required for development of Bcl6⁺ T_FH cells in vivo. These data increase our understanding of Bcl6 regulation in T_FH cells and their differentiation in vivo and identifies a new surface marker that may be functionally relevant in this subset.