The challenge of immune modulation in transplantation is to inhibit pathologic alloreactivity while minimizing off-target toxicities and preserving protective immunity. Data have emerged demonstrating the role of cellular metabolism in controlling T cell function and fate. After antigen recognition, naïve cells undergo rapid expansion, a process fueled by a switch from oxidative respiration (OXPHOS) to glycolysis. Regulation of this process is in part controlled by mTOR signaling. Studies have shown that inhibition of mTOR using rapamycin promoted OXPHOS, resulting in augmented memory generation in pathogen-elicited T cell populations. However, while rapamycin augmented the CD8⁺ T cell response in the context of an infection, it failed to do so in the setting of a transplant. Here, we hypothesized that differences in T cell bioenergetics in pathogen- vs. graft- elicited antigen-specific CD8+ T cell populations drive the paradoxical effect seen with rapamycin. To investigate this, we used a transgenic system in which both the antigen of interest and the responding monoclonal T cell population were identical. TCR-transgenic OT-I and OT-II T cells specific for OVA were transferred into recipient B6 mice. Mice were either infected with OVA-expressing gamma-herpesvirus (gHV-OVA) or grafted with an OVA-expressing skin graft. Secondary lymphoid organs were harvested at the peak of response (day 10). We found that the gHV-elicited antigen-specific CD8⁺ T cells showed higher KLRG expression as compared to the graft-elicited cells (32.4% +/- 4.5 vs. 5.5% +/- 2.1, p<0.001), suggesting an altered differentiation status in monoclonal TCR tg T cells stimulated by gHV as compared to a graft. Furthermore, our study identified metabolic differences in gHV- vs. graft-elicited T cells. First, gHV-elicited CD8⁺ T cells exhibited increased expression of the glucose transporter GLUT-1 relative to the graft-elicited T cells (MFI 2548 +/- 105 vs. 1235 +/- 117, p<0.001). Second, gHV-elicited CD8⁺ T cells exhibited an increase in CD36, a surface receptor for long-chain fatty acids (MFI 2548 +/- 105 vs. 2221 +/- 82, p=0.04), suggesting that gHV-elicited CD8+ T cells may derive more fatty acid fuel from the extracellular environment as compared to graft-elicited T cells, which may preferentially utilize intracellular sources. These data shed light on metabolic differences in T cell populations generated in response to transplant vs. infection. Future work is aimed at determining the impact of these differences on immunosuppression.

CITATION INFORMATION: Karp A, Wagener M, Robertson J, Ford M. Profiling Metabolic Differences Between Graft- vs. Pathogen-Elicited CD8⁺ T Cell Responses. Am J Transplant. 2016;16 (suppl 3).

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