Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4+ T‐cell function in rodents

T cells chronically stimulated by a persistent antigen often become dysfunctional and lose effector functions and proliferative capacity. To identify the importance of micro‐RNA‐155 (miR‐155) in this phenomenon, we analyzed mouse miR‐155‐deficient CD4⁺ T cells in a model where the chronic exposure to a systemic antigen led to T‐cell functional unresponsiveness. We found that miR‐155 was required for restoring function of T cells after programmed death receptor 1 blockade. Heme oxygenase 1 (HO‐1) was identified as a specific target of miR‐155 and inhibition of HO‐1 activity restored the expansion and tissue migration capacity of miR‐155^?/? CD4⁺ T cells. Moreover, miR‐155‐mediated control of HO‐1 expression in CD4⁺ T cells was shown to sustain in vivo antigen‐specific expansion and IL‐2 production. Thus, our data identify HO‐1 regulation as a mechanism by which miR‐155 promotes T‐cell‐driven inflammation.