Expression of CD8α identifies a distinct subset of effector memory CD4⁺ T lymphocytes

Circulating CD4⁺ CD8⁺ T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4⁺ CD8⁺ T cells in rhesus macaques. Two distinct populations of CD4⁺ CD8⁺ T cells were identified: the dominant one was CD4^hi CD8^lo and expressed the CD8αα homodimer, while the minor population was CD4^lo CD8^hi and expressed the CD8αβ heterodimer. The majority of CD4^hi CD8α^lo T cells exhibited an activated effector/memory phenotype (CCR5^lo CD7^- CD28^- HLA-DR⁺) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4^hi CD8α^lo T cells compared to single-positive CD4⁺ T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4^hi CD8α^lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4^hi CD8α^lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4⁺ T cells expressing CD8α represent an effector/memory subset of CD4 ⁺ T cells and that this cell population can be depleted during the course of SIV infection.