Date: Monday, May 4, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Memory T cells (Tmem), particularly those resistant to costimulation blockade (CoSB), are considered a major barrier to transplant tolerance. The T-box transcription factor Eomesodermin (Eomes) is critical for Tmem development and differentiation. Eomes expression by donor-specific Tmem in nonhuman primates and in allograft recipients has not been examined.
We evaluated Eomes expression by CD4+ and CD8+ Tmem in normal monkeys. The effect of CoSB using CTLA4Ig on Eomes and the co-inhibitory CTLA4 expression by alloactivated CD8+T cells was examined. In CTLA4Ig treated renal allograft recipients, with or without regulatory dendritic cell (DCreg) infusion, Eomes and CTLA4 expression by donor-reactive CD8+T cells before and after transplantation was examined.
In normal monkeys, CD8+T cells expressed significantly higher Eomes levels and lower CTLA4 levels compared to CD4+T cells. Central Tmem (Tcm) expressed higher Eomes levels than effector memory, effector and naive CD4+ and CD8+T cell subsets. Following allostimulation, distinct proliferating EomesloCTLA4hi and EomeshiCTLA4lo CD8+T cell populations were identified. Tcm comprised a high proportion of EomesloCTLA4hi CD8+T cells. CoSB with CTLA4Ig during allostimulation of CD8+T cells reduced CTLA4 expression significantly but not Eomes expression, leading to significant reduction of EomesloCTLA4hi cells.
In CTLA4Ig treated renal allograft recipients, donor-reactive EomesloCTLA4hi CD8+T cells were reduced significantly after transplantation. However, in monkeys given CTLA4Ig combined with DCreg, the frequency of EomesloCTLA4hi CD8+T cells remained similar to those pre-transplant, which was associated with strong expression of CTLA4 by graft-infiltrating CD8+T cells. In one long-surviving DCreg-treated recipient, EomesloCTLA4hi CD8+T cells were maintained transiently after immunosuppression withdrawal, followed by gradual decline, which was associated with gradual increase of EomeshiCTLA4lo CD8+T populations.
CoSB resistance of donor-reactive Tmem after transplantation may be related to reduction of EomesloCTLA4hi Tmem population. A relative increase in this population may contribute to the ability of DCreg to prolong organ allograft survival in CB-treated recipients.
To cite this abstract in AMA style:Ezzelarab M, Lu L, Guo H, Zahorchak A, Shufesky W, Cooper D, Morelli A, Thomson A. Eomesodermin Expression By Alloreactive Non-Human Primate CD8+ Memory T Cells: Influence of CTLA4Ig and Regulatory DC Infusion in Renal Allograft Recipients [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/eomesodermin-expression-by-alloreactive-non-human-primate-cd8-memory-t-cells-influence-of-ctla4ig-and-regulatory-dc-infusion-in-renal-allograft-recipients/. Accessed September 22, 2019.
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