BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis

Diverse autoimmune and allergic diseases are associated with polymorphisms in a locus encoding the transcription factor BACH2; here, BACH2 is shown to be a broad regulator of immune activation that stabilizes the differentiation of T reg cells by repressing commitment of CD4 + T cells to alternate cell fates. Anti-inflammatory action of BACH2 Polymorphisms within a locus encoding the transcription factor BACH2 are associated with a number of allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, coeliac disease and type 1 diabetes. This paper identifies a mechanism by which BACH2 might contribute to autoimmunity. Roychoudhuri et al . show how BACH2 limits autoimmunity by repressing alternative cell fates through the stabilization of the differentiation of regulatory T cells. These findings suggest a role for BACH2 as a regulator of CD4 + T-cell differentiation, preventing inflammatory disease by controlling the balance between tolerance and immunity. Through their functional diversification, distinct lineages of CD4 + T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment 1 . Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma 2 , Crohn’s disease 3 , 4 , coeliac disease 5 , vitiligo 6 , multiple sclerosis 7 and type 1 diabetes 8 . Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4 + T cells. BACH2 was required for efficient formation of regulatory (T reg ) cells and consequently for suppression of lethal inflammation in a manner that was T reg -cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during T reg polarization resulted in inappropriate diversion to effector li