Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation

Abstract

Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. Transcriptional regulators of human Tfh cell differentiation are poorly understood. In this article, we demonstrate that Bcl6 controls specific gene modules for human Tfh cell differentiation. The introduction of Bcl6 expression in primary human CD4 T cells resulted in the regulation of a core set of migration genes that enable trafficking to germinal centers: CXCR4, CXCR5, CCR7, and EBI2. Bcl6 expression also induced a module of protein expression critical for T–B interactions, including SAP, CD40L, PD-1, ICOS, and CXCL13. This constitutes direct evidence for Bcl6 control of most of these functions and includes three genes known to be loci of severe human genetic immunodeficiencies (CD40L, SH2D1A, and ICOS). Introduction of Bcl6 did not alter the expression of IL-21 or IL-4, the primary cytokines of human Tfh cells. We show in this article that introduction of Maf (c-Maf) does induce the capacity to express IL-21. Surprisingly, Maf also induced CXCR5 expression. Coexpression of Bcl6 and Maf revealed that Bcl6 and Maf cooperate in the induction of CXCR4, PD-1, and ICOS. Altogether, these findings reveal that Bcl6 and Maf collaborate to orchestrate a suite of genes that define core characteristics of human Tfh cell biology.

Follicular helper T cells may play an important role in the severity of primary Sjögren's syndrome

“…cluster of differentiation (CD)40L and signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) which are critical in T-B cell interaction [9,[12][13][14][15][16]. In the follicles, [20].…”

“…4). characteristics [13]. Moreover, co-stimulation controlled by IL-21 is necessary for high level expression of CXCR5, which is required for migration into GCs [42,43].…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Similarly, mice deficient for IRF4 lack Tfh cells and GC formation due to a T cell‐intrinsic defect in Bcl6 expression (Kwon et al , 2009; Bollig et al , 2012). c‐Maf, on the other hand, is known to cooperate with Bcl6 to induce expression of ICOS, CXCR5, and IL‐21 (Hiramatsu et al , 2010; Ise et al , 2011; Kroenke et al , 2012). c‐Maf‐deficient mice are able to develop limited numbers of Tfh cells; however, these cells express only low levels of CXCR5 (Bauquet et al , 2009).…”

Plasticity is the differentiated state of CD4 T cells

“…In the case of intestinal immunity, a reductionist hypothesis proposes that the expression of CXCR5 is sufficient to mediate CD4 1 T-cell relocation to the PP, where they are exposed to reduced IL2 concentrations and activated by B cells, resulting in reduced STAT5, repressed BLIMP1 and the upregulation of BCL6. BCL6 binds to the promoters of T-bet and RORct, thereby repressing IFN-c and IL17 production (but not IL4 40 ). The removal of STAT5/ BLIMP1 repression also results in the expression of c-MAF, BATF, and IL21, and increased expression of BCL6 induces expression of proteins involved in T-B interactions, including SAP, CD40L, PD-1, ICOS and CXCL13 40 (reviewed in Liu et al 41 ).…”

“…BCL6 binds to the promoters of T-bet and RORct, thereby repressing IFN-c and IL17 production (but not IL4 40 ). The removal of STAT5/ BLIMP1 repression also results in the expression of c-MAF, BATF, and IL21, and increased expression of BCL6 induces expression of proteins involved in T-B interactions, including SAP, CD40L, PD-1, ICOS and CXCL13 40 (reviewed in Liu et al 41 ). As the IL17-expressing CD4 1 T cells that home to PP and convert to T FH cells express higher levels of ICOS and CD40L than the other cells there, it is possible that T FH cells differentiating from this source may have an advantage in providing Bcell help.…”