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Murine CD4 T Cells Selected in a Highly Disparate Xenogeneic Porcine Thymus Graft Do Not Show Rapid Decay in the Absence of Selecting MHC in the Periphery¹

Jose-Ignacio Rodriguez-Barbosa^2,*, Yong Zhao^*, Guiling Zhao^*, Angel Ezquerra and Megan Sykes^3,*

^* Transplantation Biology Research Center, Bone Marrow Transplantation Section, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129; and Department of Biotechnology, National Institute of Agriculture Research, Carretera de la Coruña, Madrid, Spain

CD4 repopulation can be achieved in T cell-depleted, thymectomized mice grafted with xenogeneic porcine thymus tissue. These CD4 T cells are specifically tolerant of the xenogeneic porcine thymus donor and the recipient, but are positively selected only by porcine MHC. Recent studies suggest that optimal peripheral survival of naive CD4 T cells requires the presence of the same class II MHC in the periphery as that of the thymus in which they were selected. These observations would suggest that T cells selected on porcine thymic MHC would die rapidly in the periphery, where porcine MHC is absent. Persistent CD4 reconstitution achieved in mice grafted with fetal porcine thymus might be due to increased thymic output to compensate for rapid death of T cells in the periphery. Comparison of CD4 T cell decay after removal of porcine or murine thymic grafts ruled out this possibility. No measurable role for peripheral murine class II MHC in maintaining the naive CD4 pool originating in thymic grafts was demonstrable. However, mouse class II MHC supported the conversion to, survival, and/or proliferation of memory-type CD4 cells selected in fetal porcine thymus. Thus, the same MHC as that mediating positive selection in the thymus is not critical for maintenance of the memory CD4 cell pool in the periphery. Our results support the interpretation that xenogeneic thymic transplantation is a feasible strategy to reconstitute CD4 T cells and render recipients tolerant of a xenogeneic donor.

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