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-γ (IFN-γ) may be an important mediator of rejection under these circumstances. Methods. We transferred CD4⁺ T cells from IFN-γ-deficient (IFN-γ -/-) 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-γ. Results. IFN-γ-/- 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-γ.