Naturally occurring CD4+ Foxp3+ regulatory T (Treg) cells are indispensable for preserving immune homeostasis and suppressing autoimmune pathology. Development and maintenance of Tregs depend on the transcription factor Foxp3. Under inflammatory conditions, Treg cells undergo stimulus-specific differentiation that is regulated by transcription factors typically associated with the differentiation of conventional CD4+ T cells. Our lab has recently shown that a distinct population of Tregs expresses markers consistent with an effector phenotype and is defined by the expression of the transcription factor Blimp1 and the production of high amounts of IL-10 (termed eTregs).
The transcription factor Bach2 is known as an upstream repressor of Blimp1 in B cell to plasma cell development but its function in the T cell compartment, albeit being expressed at comparable levels, is insufficiently understood. It was recently suggested that Bach2 represses the differentiation of multiple CD4+ effector lineages in the periphery and favours the development of Tregs (Roychoudhuri et al, Nature 2013). Surprisingly, Foxp3 induction in vitro and Treg numbers in vivo were diminished but stability of Foxp3 in existing Tregs was unaffected. Moreover, Bach2-deficient Treg cells were fully functional to suppress T cell proliferation in vitro but could not ameliorate colitis induced by adoptive transfer of naïve T cells into lymphopenic hosts.
Using broad transcriptional profiling of Tregs, we have observed tight regulation of Bach2 during eTreg differentiation and have found that deletion of Bach2 results in increased eTreg development. Furthermore, we found that Bach2 was required for efficient formation of thymic Tregs. Therefore, we hypothesise that Bach2 controls differentiation of Tregs during at least two distinct stages during their development. Using novel conditional Treg-specific Bach2-deficient and Bach2 reporter mice we are currently dissecting the role of Bach2 in thymic and peripheral Tregs in more detail.