*Purpose: Despite advances in the survival of transplanted organs, acute T cell mediated rejection remains a significant clinical problem with few effective or targeted treatments. The differentiation of naïve CD8⁺ T cells into effector populations is governed by cues that occur during antigen priming. Therefore, understanding the characteristics of CD8⁺ T cell differentiation in response to allogeneic antigen has the potential to uncover strategies that could selectively restrain donor-reactive T cell responses.

*Methods: In order to gain a detailed understanding of the differentiation of endogenous CD8⁺ T cells in response to allografts, we evaluated the C57BL/6 H-2(b) CD8⁺ T cell response to an allogeneic H-2L(d)-restricted epitope (termed “QL9”) using an MHC class I tetramer. Using a magnetic enrichment method, we established that the QL9/L(d) tetramer specifically stained naïve CD8+ T cells in a peptide-dependent manner.

*Results: Following skin grafting with H-2L(d)-expressing Balb/c skin grafts, the absolute number of QL9/L(d)-specific CD44^hi CD8⁺ T cells expanded approximately 10-fold relative to naïve mice, and nearly all of the CD44^hiQL9/L(d)-specific cells were Ki67⁺ at day 10 in the draining lymph node and spleen. In infection models, the expression of KLRG-1 and CD127 (IL-7Rα) on effector CD8⁺ T cell populations correlates with divergent cellular fates as either short-lived effectors (KLRG-1^hiCD127^lo) or memory T cells (KLRG-1^loCD127^hi). We next evaluated the phenotype of QL9/L(d)-specific effector cells during the first two weeks post-graft. The expression of CD127 declined acutely at day 7 post-graft and was re-expressed by day 14, similar to the kinetics of expression on post-infection viral-specific CD8⁺ T cells. However, in contrast to the high frequency of KLRG-1^hi short-lived effector cells that emerge post-infection, following skin grafting a very low frequency of QL9/L(d)-specific cells were KLRG-1^hi (avg. 4.4% and 8.5% in draining lymph nodes and spleen, respectively).

*Conclusions: These results suggest that a significant portion of allogeneic short-lived effector CD8+ T cells have a KLRG-1lo phenotype that is distinct from the established population definitions. Future studies will investigate the subpopulations of KLRG-1lo QL9/L(d)-specific effector CD8+ T cells that have potent effector function, with the goal of identifying novel cellular pathways that might serve as effective therapeutic targets.

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