As Tmem are known barriers to transplant survival and tolerance in animals and human transplant recipients, understanding factors that drive the formation and survival of Tmem is essential. Building upon data that immune cell-derived complement components C3a and C5a bind to their receptors (C3aR/C5aR respectively) to amplify CD4 T effector (Teff) cell expansion, we tested the impact of C3aR and C5aR signaling on alloreactive CD8 Teff and Tmem expansion and persistence. We transplanted fully MHC-disparate BALB/c hearts into WT, C3aR-/-, and C5aR-/- B6 recipients without immunosuppression, and quantified numbers/frequencies of donor-reactive IFNg-producing CD8 T cells by flow cytometry and ELISPOT on posttransplant d 6 (during acute rejection), d 90 and beyond d 180 (persistent memory). All grafts were rejected by d 10. Expanding upon previous studies of CD4 T cells, acute donor-reactive CD8 Teff expansion on d 6 in C3aR-/- or C5aR-/- was <50% of that in WT controls (WT 9.8×10^5, C3aR-/- 2.8×10^5, p=0.02, C5aR-/- 4.7×10^5, p<0.01). In WT, the numbers of donor-reactive Tmem cells on d 90 were <50% of the d 6 response (p<0.01), although higher than in naïve mice (p=0.02), demonstrating contraction of the Teff repertoire leaving Tmem as the immune stimulus wanes. In C3aR-/- recipients the numbers of splenic donor-reactive CD8 cells on d 90 were remarkably similar to those detected on d 6 (no contraction, p=0.7). We in fact detected higher numbers of donor-reactive Tmem cells in C3aR-/- vs WT on d 90 (WT 1.4×10^5, C3aR-/- 2.7×10^5, p<0.01). Analysis beyond d 180 showed continued persistence of alloreactive Tmem in C3aR-/- recipients. In contrast, the number of donor-reactive CD8 cells was lower in C5aR-/- recipients on d 90 and 180 (vs d6 p<0.05 for each). Preliminary studies using animals in which only alloreactive CD8 T cells were deficient in C3aR or C5aR showed similar effects on Tmem persistence. Mechanistic biochemical analyses revealed C3aR and C5aR signaling on CD8 T cells triggers mTORC1 activation, tying C3aR- and C5aR-dependent Teff expansion to known metabolic signaling pathways. Our findings uniquely show that blocking C3aR or C5aR signaling uncouples Teff from Tmem formation/persistence and that the two receptors have different effects on the longterm persistence of Tmem, results that have important implications for vaccination and transplantation.

CITATION INFORMATION: Mathern D, Heeger P. Absence of Receptors for C3a or C5a Prevent Alloreactive CD8 T Effector Cell (Teff) Expansion but Differentially Impact Memory (Tmem) Persistence Posttransplantation. Am J Transplant. 2016;16 (suppl 3).

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