CD8 T Cells Specific for a Donor-Derived, Self-Restricted Transplant Antigen Are Nonpathogenic Bystanders after Vascularized Heart Transplantation in Mice

Abstract

CD8 T cell cross-priming, an established mechanism of protective antiviral immunity, was originally discovered during studies involving minor transplantation Ags. It is unclear whether or how cross-primed CD8 T cells, reactive to donor-derived, but recipient class I MHC-restricted epitopes, could injure a fully MHC-disparate, vascularized transplant. To address this question we studied host class I MHC-restricted, male transplantation Ag-reactive T cell responses in female recipients of fully MHC-disparate, male heart transplants. Cross-priming to the immune-dominant determinant HYUtyp occurred at low frequency after heart transplantation. CD8 T cell preactivation through immunization with HYUtyp mixed in CFA did not alter the kinetics of acute rejection. Furthermore, neither HYUtyp immunization nor adoptive transfer of HYUtyp-specific TCR-transgenic T cells affected outcome in 1) a model of chronic rejection in the absence of immunosuppression or 2) a model of allograft acceptance induced by costimulatory blockade. The results support the contention that CD8 T cells reactive to host-restricted, but donor-derived, Ags are highly specific and are nonpathogenic bystanders during rejection of MHC-disparate cardiac allografts.

CD4+ T Lymphocytes Are Not Necessary for the Acute Rejection of Vascularized Mouse Lung Transplants

“…CD8 ϩ T lymphocytes can also recognize exogenous Ag presented in the context of self-MHC class I molecules (52). However, recent studies have indicated that indirectly primed CD8 ϩ T cells do not play a major role in shaping immune responses to allografts (53).…”

The importance of the indirect pathway of allorecognition in clinical transplantation

“…There is now evidence, however, that CD8 T cells can also have indirect allospecificity owing to the phenomenon of 'cross-priming', whereby APCs can take up proteins (including alloantigen) shed by surrounding cells, and present them in peptide form in the context of self MHC class I molecules. Heeger's group showed that recipient CD8 + T cells primed by endothelial cells in this way could effect rejection of skin grafts [19 ]; more recently, however, the group has found that these 'indirect' pathway CD8 + cells have no effect on rejection or tolerance of vascularized cardiac allografts in a TCR transgenic MHC-disparate model [20]. The significance of this pathway of indirect recognition therefore remains unclear.…”

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus

“…This kind of response, while consistent with many general studies of peripheral T cell tolerance, would not have been expected based on the transplantation literature. Rather, indirectly alloreactive T cells can be primed to both skin and heart transplants, even in experimental situations where direct allorecognition is absent (5,7,(40)(41)(42)(43)(44). One possibility for the differential behavior of the fetus versus surgical organ transplants is that pregnancy may lack the local and/or systemic inflammatory response associated with surgery.…”