Bcl6 BTB Repressor Domain Function Differentiation Is Defective in the Absence of Cutting Edge: T Follicular Helper Cell

T follicular helper (Tfh) cells are essential for germinal centers (GCs) and most long-term humoral immunity. Differentiation of Tfh cells depends on the transcrip-tional repressor B cell CLL/lymphoma 6 (Bcl6). Bcl6 mediates gene repression via the recruitment of corepres-sors. Currently, it is unknown how Bcl6 recruits core-pressors to regulate gene expression of Tfh cells. In this article, we demonstrate, using a mutant form of Bcl6 with two BTB (bric-a-brac, tramtrack, broad-complex) mutations that abrogate corepressor binding, that the Bcl6 BTB domain is required for proper differentiation of Tfh and GC-Tfh cells in vivo. Importantly, we also observe a significant defect in GC B cell development. These results are consistent in multiple contexts, including a novel lymphocytic choriomeningitis virus nucleoprotein-specific TCR-transgenic mouse model. Taken together, these data suggest that the Bcl6 BTB domain is a key mediator of the differentiation of Tfh cells. T he transcriptional repressor B cell CLL/lymphoma 6 (Bcl6) is essential for the differentiation of T follicular helper (Tfh) cells and germinal center (GC) B cells. Tfh cells are CD4 T cells specialized in providing help for B cells (1). The absence of Tfh cells results in the loss of GCs and, consequently, abrogated memory B cell, plasma cell, and neutralizing Ab responses. Thus, Tfh cells have critical roles in protective immune responses against pathogens, as well as deleterious roles in numerous autoimmune diseases (1, 2). Bcl6 consists of a bric-a-brac, tramtrack, broad-complex (BTB/POZ) domain, a middle domain (also known as RDII), and a zinc finger domain consisting of six Kruppel-like zinc fingers (1). BTB domains are evolutionarily conserved protein-interaction domains that are widely present in transcription factors (3, 4). The BTB domain forms the interface of the obligate homodimer, and the corepressors BCOR, SMRT, and NCOR bind at the cleft formed by this interface (5–8). Although Bcl6 is required for Tfh cell differentiation (9–12), the contributions of its functional domains in CD4 + T cells are not well understood. In this study, we sought to examine the role of the Bcl6 BTB domain in Tfh cell differentiation and function. Mice and vectors C57BL/6J (B6) and Cre CD4 mice were purchased from The Jackson Laboratory. Bcl6 fl/fl (13), CD45.1-congenic, and Smarta TCR–transgenic (SM; specific for lymphocytic choriomeningitis virus [LCMV] gp66–77 on I-A b) (14) mice were on a full B6 background and were bred at the La Jolla Institute for Allergy and Immunology. Bcl6 BTBMUT mice, engineered to …