Type 2 immune deviation has differential effects on alloreactive CD4⁺ and CD8⁺ T cells

Allograft rejection has been associated with detection of the type 1 lymphokines, IFN-γ and IL-2. The role of type 2 cytokines (IL-4 and IL-5) remains controversial, as is whether alloreactive CD4⁺ and CD8⁺ T cells behave similarly when exposed to type 2 cytokine-enhancing manipulations. We studied the characteristics of alloreactive CD4⁺ and CD8⁺ T cells before and after type 2 immune deviation induced by IL-4 plus anti-IFN-γ Ab. Alloreactive T cells from naive mice were low in frequency, produced only IL- 2, and were predominantly CD4⁺, while alloreactive T cells from allograft- primed mice were high in frequency, produced IFN-γ, IL-2, and IL-4, and were predominantly CD8⁺. Type 2 immune deviation of allospecific CD4⁺ T cells resulted in IL-4 and IL-5 production without IFN-γ, consistent with unipolar type 2 immunity. These T cells mediated delayed-type hypersensitivity, but not cytotoxicity. Under identical type 2 cytokine-inducing conditions, allospecific CD8⁺ T cells were primed to become IL-4, IL-5, and IFN-γ producers, and exhibited cytotoxicity, but not classic delayed-type hypersensitivity. Adoptive transfer of either cell population into SCID recipients of allogeneic skin resulted in graft rejection, with stable allospecific type 2 cytokine production in vivo. Adoptive transfer of the IL- 4/IL-5-producing CD4⁺ T cells, but not the CD8⁺ T cells, induced a distinct histopathology characterized by marked eosinophilic infiltration of the skin. We conclude that type 2 immune deviation has differential effects on CD4⁺ and CD8⁺ T cells and results in emergence of alternate effector mechanisms capable of destroying allografts.