Grace Nauman, M.A., M. Phil.
Columbia Center for Translational Immunology, Department of Medicine; Columbia University Department of Microbiology and Immunology, Columbia University Medical Center
Porcine thymic transplantation is a promising approach for tolerance induction in pig-to-human xenotransplantation. In immunodeficient mice transplanted with human CD34+ cells, porcine thymus grafts support selection of a diverse, pig-tolerant human T cell repertoire. However, human T cells developing in a swine thymus may show reduced human-restricted vaccination responses compared to those from a human thymus. To understand the impact of positive selection in a swine thymus on human-restricted TCRs, we used a TCR transgenic humanized mouse model to study selection of Mart1, a human HLA-A2-restricted TCR, in a pig thymus. Mart1 was positively selected inefficiently in a human HLA-A2- or pig thymus compared to an HLA-A2+ thymus. While proportions of GFP reporter+ thymocytes were similar (A2+:15.0±6.46%; A2-:19.2±5.85%; Sw:11.2±6.73%; n.s. by one-way ANOVA), Mart1+ and CD8SP Mart1+ thymocytes were enriched in A2+ compared to A2- and swine thymi (A2+:3.51±0.553%; A2-:1.25±0.583%; Sw:0.629±0.481%; A2+ vs. A2-, p=0.049; A2+ vs. Sw, p=0.010; and A2+:2.28±0.591; A2-:0.261±0.057; Sw:0.342±0.236, A2+ vs. A2-, p=0.034; A2+ vs. Sw, p=0.029, respectively). However, Mart1+ cells were detected in the periphery at similar frequencies among GFP+ cells in all groups (CD4: A2+:10.3±6.25%; A2-:6.69±2.49%; Sw:4.53±1.69%; CD8: A2+:41.5±11.6%; A2-:45.5±15.6%; Sw:12.1±7.22%; n.s.) and could proliferate when pulsed with peptide ex vivo. Possibly, the few T cells with human-restricted TCRs that were positively selected in a swine thymus received adequate postthymic signals for normal homeostasis in transplanted mice. These results suggest that, while positive selection of human-restricted T cells in a transplanted pig thymus may be inefficient, those that are selected may function normally.