CD4+ T cells responsive through the indirect pathway can mediate skin graft rejection in the absence of interferon-γ

Background. T cells responding through the indirect pathway can induce allograft rejection, but mechanisms of rejection are not known. Interferon-gamma (IFN-gamma) may be an important mediator of rejection under these circumstances. Methods. We transferred CD4(+) T cells from IFN-gamma-deficient (IFN-gamma -/-) mice into SCID recipients of MHC II-deficient (MHC II -/-) skin grafts. Under these conditions, rejection can only occur via the indirect pathway and cannot be mediated by T-cell production of IFN-gamma. Results. IFN-gamma -/- CD4(+) T cells rejected MHC II -/- skin grafts. Flow cytometry revealed only CD4(+) T cells in the recipients. Cytokine enzyme-linked immunosorbent spot assays confirmed only indirect recognition with an associated expansion of an alloreactive population of IL-2-, IL-4-, and IL-5-secreting T cells. Conclusion. CD4(+) T cells recognizing alloantigens via the indirect pathway can mediate skin graft rejection in the absence of IFN-gamma.