*Purpose: Potent CD4⁺CD8α^lo effector T cells have been reported in transplant (tx) patients. . We evaluated the incidence and function of CD4⁺CD8α^loT cells in renal allograft recipient monkeys treated with costimulation blockade.

*Methods: Peripheral blood mononuclear cells were isolated from naïve and transplanted rhesus monkeys (n=4) and stained for analysis of cell surface and intracellular marker expression by flow cytometric and Imagestream analysis. CD4⁺CD8α^– and CD4⁺CD8α^lo T cells were assessed for expression of memory T cell subset markers while effector function was determined by interferon-gamma (IFNg) and tumor necrosis factor-alpha (TNFα) production. Transplant recipients receivedCTLA4Ig and Tacrolimus immunosuppression. Proliferation and cytokine production of donor-reactive CD4⁺CD8α^– and CD4⁺CD8α^lo T cells were evaluated before and after tx (2-4 weeks) in CFSE-MLR. CD4⁺CD8α^– and CD4⁺CD8α^lo T cells were also characterized in grafts at the time of rejection.

*Results: In naïve monkeys, circulating CD4⁺CD8α^lo T cells comprised significantly higher percentages of memory subsets (p<0.01), and IFNg⁺TNFa⁺ cells (p<0.01) compared to CD4⁺CD8α^– T cells. In allograft recipients, the incidences of circulating CD4⁺CD8α^– and CD4⁺CD8α^lo T cells did not increase after tx. Following ex vivo stimulation with donor cells, CD4⁺CD8α^lo cell proliferation was higher than CD4⁺CD8α^– cell proliferation, both before and after tx. Before tx, mean percentages of IFNg⁺TNFa⁺ cells in the CD4⁺CD8α^lo population (20.4%) were higher than that in the CD4⁺CD8α^– population (9.2%). After tx, the mean percentage of IFNg⁺TNFa⁺ cells in the CD4⁺CD8α^lo T cell population (24.3%) was significantly higher than that in the CD4⁺CD8α^– population (6.4%) (p<0.05). Notably, the percentage of graft-infiltrating CD4⁺CD8α^lo T cells ranged from 1.33 – 3.39%.

*Conclusions: In CTLA4Ig/Tacrolimus-treated renal allograft recipient monkeys, donor-reactive CD4⁺CD8α^lo T cells exhibit higher proliferative capacity and proinflammatory cytokine production compared to CD4⁺CD8α^– T cells identifying the former as more potent effector cells.

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