Memory T cell (Tm) homeostasis is poorly understood and is a critical challenge to controlling transplant rejection. At present there are no effective clinical strategies to control Tm and contradictory reports exist as to their control by regulatory T cell (Treg). We previously found that TCRΑΒ+CD3+CD4–CD8–NK1.1– (double-negative, DN)-Treg could effectively suppress CD4+ and CD8+ effector T cells and thus mitigate transplant rejection. We utilized this model to test whether DN-Tregs could similarly suppress Tm. Tm was generated by immunizing mice with allogeneic spleen cells. Interestingly DN-Tregs suppressed CD8+ Tm by >53% but had no effect on CD4+ Tm cells. As well DN-Tregs express very high levels of granzyme B (GzmB), suggesting a potential control mechanism and indeed no suppression was observed using perforin null DN-Tregs. In BALB/c (H-2d) to B6-Rag1-/- mice (H-2b) skin allograft transplantation, DN-Tregs suppressed CD8+CD44high Tm mediated rejection and significantly prolonged graft survival over CD8+ Tm cell transfer alone (63.0±4.7 days, vs. 21.5±1.7 days, p<0.05). In contrast, co-transfer of DN-Tregs had no effect on CD4+CD44high Tm mediated rejection (25.3±1.4 days, vs. 20.0±0.7 days, p>0.05). DN-Tregs co-transferred with CD8+ Tm had significantly reduced total CD44high CD8+ Tm (10.9×104 vs. 27.9×104), CD44high CD62Lhigh central Tm (6.2×104 vs. 13.1×104), and CD44high CD62Llow effector Tm (4.7×104 vs. 14.8×104) in spleens (n=3, p<0.05). There was no effect with co-transferred CD4+ Tm. CD4+ Tm cells express higher levels of GzmB inhibitory Serpin Protease Inhibitor 6 (SPI-6) mRNA (7.7-fold) and have higher intracellular expression of SPI-6 protein than CD8+ Tm (5.2-fold) (p<0.05, n=3), suggesting CD4+ Tm may escape DN-Treg control by resistance to GzmB. We show for the first time, that DN-Treg can control CD8+ Tm and suggest that DN-Treg along with targeting SPI-6 may be useful to limit the expansion of Tm in transplantation.
To cite this abstract in AMA style:Su Y, Huang X, Lian D, Min W, Jevnikar A, Zhang Z. CD4+ but Not CD8+ Memory T Cells Escape Granzyme B Mediated Regulation by DN-Treg [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/cd4-but-not-cd8-memory-t-cells-escape-granzyme-b-mediated-regulation-by-dn-treg/. Accessed July 30, 2021.
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