The SLAM family receptor 2B4 is expressed primarily on NK cells and memory CD8+ T cells. In prior studies, we found that 2B4 was upregulated on primary murine CD8+ donor-reactive effector T cells in the setting of CD28 blockade and played a functional role in attenuating this response during allograft rejection. However, in these studies 2B4 was found not to be expressed within the CD4+ T cell compartment, either on endogenous T cells or on TCR transgenic graft-specific CD4+ primary effectors. Interestingly, during the course of our studies examining 2B4 expression on CD8+ T cells in healthy controls and renal transplant recipients, we noted significant expression of 2B4 on human CD4+ T cells. In human PBMCs obtained from healthy controls, 2B4 expression was observed only on CD45RA- CD4+ T cells, and further these 2B4+ CD4+ cells were exclusively CCR7- and CD127-, consistent with a terminal differentiation status. In order to determine whether this discrepancy was an inherent difference between mice and humans or a reflection of immunologic experience in humans as compared to laboratory animals, we infected naive B6 animals with both LCMV and Listeria in order to generate immunologically experienced mice, and analyzed the CD4+ T cell compartment in distinct lymphoid tissues. Results revealed that 2B4 was expressed on 2.2% of total splenic CD4+ T cells by day 40 post infection. Expression was enriched within the splenic CD44hi CD4+ T cell population (6.5% on CD44hi vs 0.49% on CD44lo). Interestingly, the 2B4+ CD4+ population was confined to the bone marrow and spleen, and was absent from peripheral lymph nodes and blood. To interrogate the function of 2B4+CD4+ T cells, healthy donor human PBMCs were restimulated in vitro for six hours with anti-CD3 and anti-CD28 beads. Compared to 2B4- CD4+ cells, human 2B4+ CD4+ T cells exhibited reduced production of IL-2 and IFN-gamma, which may be indicative of cellular exhaustion. In conclusion, 2B4 is expressed on human and mouse CD4+ memory T cells, and its expression in human cells correlates with decreased cytokine secretion. The potential role of 2B4 is modulating alloreactive CD4+ memory T cell responses warrants further investigation.

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