Abstract
The transcription factor Bach2 is a susceptible gene for numerous autoimmune diseases including systemic lupus erythematosus (SLE). Bach2−/− mice can develop a lupus-like autoimmune disease. However, the exact cellular and molecular mechanisms via which Bach2 protects the hosts from developing autoimmunity remains incompletely understood. Here, we report that Bach2 ablation on T cells, but not B cells, resulted in humoral autoimmunity, and this was associated with expansion of T follicular helper (Tfh) cells and abnormal germinal centers. Bach2 was down-regulated in Tfh cells and directly suppressed by the Tfh-defining transcription factor BCL6. Mechanistically, Bach2 directly suppresses the transcription of Cxcr5 and c-Maf, two key regulators of Tfh cell differentiation. Bach2-deficient Tfh cells were skewed toward the IL-4-producing subset, which induced IgG1 and IgE isotype switching of B cells. Heterozygous Bcl6 deficiency reduced the formation of germinal center and autoantibodies, and ameliorated the pathology in Bach2-deficient mice. Our findings identify Bach2 as a crucial negative regulator of Tfh cells at steady state and prove that Bach2 controls autoimmunity in part by restraining accumulation of pathogenic Tfh cells.
Highlights
The transcription factor Bach2 belongs to the BTB and Cap’n’collar (CNC) gene family and functions within multiple innate and adaptive lineages to control immune responses [1]
We report that genetic deletion of Bach2 in T cells, but not in B cells, recapitulated the lupus-like autoimmunity in Bach2−/− mice
To determine which types of immune cells play key roles in disease development, we generated cell-type-specific Bach2-deficient mice where Bach2 was deleted in CD4+ T cells (Bach2 CD4) or B cells (Bach2 CD19)
Summary
The transcription factor Bach belongs to the BTB and Cap’n’collar (CNC) gene family and functions within multiple innate and adaptive lineages to control immune responses [1]. Genetic polymorphisms within the BACH2 gene locus in human are associated with numerous autoimmune and allergic diseases including asthma [2], vitiligo [3], multiple sclerosis [4], type I diabetes [5], and systemic lupus erythematosus (SLE) [6]. Bach is highly expressed in GC B cells and promotes antibody class switching and suppresses plasma cell differentiation [8, 9]. Bach is expressed by T cells, and directs T helper (Th) cell differentiation, homeostasis, and effector functions [1]. Bach constrains full effector differentiation within Th1, Th2, and Th17 cells in vitro [7].
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