217: BACH2 represses effector differentiation and cytokine expression to stabilize Treg-mediated immune homeostasis

Abstract

Through their functional diversification, distinct lineages of CD4 + T cells play key roles in either driving or constraining 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. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn’s disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. While these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2in the maintenance of immune homeostasis had not been established. We have found that BACH2 plays a broad role in maintaining immune homeostasis, by stabilizing T reg -mediated immunoregulatory capacity while repressing the differentiation programmes 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 lineages and aberrant expression of effector cytokines. Remarkably, blockade of effector cytokines IFN-γ and IL-4 during iTreg cell polarization could restore FoxP3 expression amongst BACH2-deficient cells. In addition, BACH2constrained full effector differentiation and production of IFN-γ, IL-13 and IL17-A in Th1, Th2 and Th17 cell lineages, respectively. These findings identify BACH2 as a key regulator of CD4 + T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.