miR-155 Promotes T Follicular Helper Cell Accumulation during Chronic, Low-Grade Inflammation

• miR-155 is necessary for spontaneous Tfh cell accumulation in Mir146a−/− mice
• miR-155 promotes differentiation of naive T cells into Tfh cells
• miR-155 directly targets multiple regulatory genes in Tfh cells
• miR-155 plays a T cell-intrinsic role during Tfh cell formation in Mir146a−/− mice

SummaryChronic inflammation is a contributing factor to most life-shortening human diseases. However, the molecular and cellular mechanisms that sustain chronic inflammatory responses remain poorly understood, making it difficult to treat this deleterious condition. Using a mouse model of age-dependent inflammation that results from a deficiency in miR-146a, we demonstrate that miR-155 contributed to the progressive inflammatory disease that emerged as Mir146a−/− mice grew older. Upon analyzing lymphocytes from inflamed versus healthy middle-aged mice, we found elevated numbers of T follicular helper (Tfh) cells, germinal center (GC) B cells, and autoantibodies, all occurring in a miR-155-dependent manner. Further, Cd4-cre Mir155fl/fl mice were generated and demonstrated that miR-155 functions in T cells, in addition to its established role in B cells, to promote humoral immunity in a variety of contexts. Taken together, our study discovers that miR-146a and miR-155 counterregulate Tfh cell development that drives aberrant GC reactions during chronic inflammation.