Pivotal Advance: Heme oxygenase 1 expression by human CD4+ T cells is not sufficient for their development of immunoregulatory capacity.

HO-1 is the only inducible one of three isoenzymes that catalyzes the oxidative degradation of heme. HO-1 is inducible by various cellular stress factors and exerts cytoprotective and immunomodulatory effects. Recent publications demonstrated that HO-1 is constitutively expressed by CD4(+)CD25(+) T(regs) and induced in CD4(+)CD25(-) T cells upon FoxP3 transfection. Here, we investigated whether HO-1 was essential and sufficient for human T(regs) to exert immunosuppression in vitro. PGJ(2) induced pronounced expression of HO-1 in CD4(+)CD25(-) T cells without accompanying FoxP3 induction. Treatment of CD4(+)CD25(-) T cells with PGJ(2) decreased their proliferation, whereas the HO-1 inhibitor SnPP enhanced the proliferation of HO-1-expressing T(regs), suggesting that HO-1 may modulate the proliferative capacity of T lymphocytes. HO-1 modulation by SnPP treatment of T(regs) or PGJ(2) treatment of CD4(+)CD25(-) T cells neither suppressed nor induced immune-modulatory function in these cells, respectively, as measured by responder-cell proliferation and/or IL-2 production. In summary, these data suggest that HO-1 expression by T(regs) might contribute to their typical reluctance to proliferate but does not account independently for their suppressive functions.