Opposing effects of ICOS on graft-versus-host disease mediated by CD4 and CD8 T cells

ICOS, a CD28 family member expressed on activated CD4⁺ and CD8⁺ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4⁺ or CD8⁺ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS^-/- CD4⁺ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS^-/- CD4⁺ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS^-/- CD4⁺ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS ^-/- CD8⁺ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deicient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8⁺ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS^-/- CD8⁺ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4⁺ and CD8⁺ T cells in GVHD.