Background:

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.

Methods:

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.

Results:

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 Eomes^loCTLA4^hi and Eomes^hiCTLA4^lo CD8⁺T cell populations were identified. Tcm comprised a high proportion of Eomes^loCTLA4^hi 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 Eomes^loCTLA4^hi cells.

In CTLA4Ig treated renal allograft recipients, donor-reactive Eomes^loCTLA4^hi CD8⁺T cells were reduced significantly after transplantation. However, in monkeys given CTLA4Ig combined with DCreg, the frequency of Eomes^loCTLA4^hi 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, Eomes^loCTLA4^hi CD8⁺T cells were maintained transiently after immunosuppression withdrawal, followed by gradual decline, which was associated with gradual increase of Eomes^hiCTLA4^lo CD8⁺T populations.

Conclusions:

CoSB resistance of donor-reactive Tmem after transplantation may be related to reduction of Eomes^loCTLA4^hi Tmem population. A relative increase in this population may contribute to the ability of DCreg to prolong organ allograft survival in CB-treated recipients.

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