Normal immune responses stimulated by pathogenic and environmental antigens generate memory T cells that react with donor antigens and no currently used immunosuppressive drug completely inhibits memory T cell function. While donor-reactive memory T cells clearly compromise graft outcomes, mechanisms utilized by memory T cells to promote rejection are largely unknown. We investigated how early endogenous memory cells infiltrate and express effector function in cardiac allografts. Endogenous CD8 memory T cells in non-sensitized recipients distinguish syngeneic vs. allogeneic cardiac allografts within 24 hours of reperfusion. CD8-dependent production of IFN-γ and CXCL9/Mig was observed 24-72 hours post-transplant in allografts but not isografts. CXCL9 was produced by donor cells in response to IFN-γ made by recipient CD8 T cells reactive to donor class I MHC molecules. Activated CD8 T cells were detected in allografts at least three days before donor-specific effector T cells producing IFN-γ were detected in the recipient spleen. Early inflammation mediated by donor-reactive CD8 memory T cells greatly enhanced primed effector T cell infiltration into allografts.
T cell responses are controlled by regulated expression of co-stimulatory receptors on the surface of T cells and regulated expression of co-stimulatory ligands in secondary lymphoid organs and peripheral tissues. We have tested the role of ICOS co-stimulation in eliciting effector function from endogenous graft-infiltrating CD8 memory T cells with donor-reactivity. ICOS is not expressed on the cell surface of circulating CD8 memory T cells but is rapidly up-regulated during cell division within the allograft parenchyma. Donor-reactive CD8 memory T cell infiltration, proliferation, and ICOS expression are regulated by donor class I MHC molecule expression. ICOS blockade significantly reduced IFN-γ production and other pro-inflammatory functions of the activated CD8 memory T cells. Our data demonstrate that this induction of ICOS expression within peripheral tissues is an important feature of CD8 memory T cell activation and identify ICOS as a specific target for neutralizing pro-inflammatory functions of endogenous CD8 memory T cells.
Collectively, our results suggest that strategies for optimal inhibition of alloimmunity should include neutralization of graft-infiltrating CD8 memory T cells within a very narrow window after transplantation.