Heme oxygenase-1 modulates the allo-immune response by promoting activation-induced cell death of T cells

ABSTRACT Heme oxygenase‐1 (HO‐1), which degrades heme into three products (carbon monoxide, free iron, and biliverdin), plays a protective role in many models of disease via its anti‐inflammatory, anti‐apoptotic, and anti‐proliferative actions. Overexpression of HO‐1 has been shown to suppress immune responses and prolong the survival of allografts; however, the underlying mechanism is not clear. We demonstrate two “new” properties of HO‐1 that mediate activation induced cell death (AICD) of allo‐antigen‐responsive murine CD4+ T cells, resulting in immunomodulation. First, it functions in vivo and in vitro to “boost” the proliferative response of CD4+ T cells to allo‐antigens in the early phase of allo‐antigen‐driven immune responses. This “boosting” effect is accompanied with a significant increase of activation markers and IL‐2 production. Second, it exerts a pro‐apoptotic effect in those activated T cells after the initial burst of proliferation. We further show that the AICD effect is mediated through the Fas/CD95‐FasL signal transduction pathway. Correlating with the above‐mentioned findings is the observed prolongation of mouse heart graft survival when HO‐1 is expressed in vivo in both donor and recipient. In conclusion, induction of HO‐1 expression accelerates clonal deletion of peripheral alloreactive CD4+ T cells by promoting AICD, which is presumably a key mechanism for its immunomodulatory effects such as in prolonging the survival of transplanted organs.