Background:  Circulating T lymphocytes co-expressing CD4⁺ and CD8⁺ have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of CD4⁺CD8⁺ T cells remain poorly understood. 

Methods and Results:  We identified 2 distinct populations of CD4⁺CD8⁺ T cells in rhesus macaques:  the dominant one was CD4^hiCD8^low and expressed the CD8aa homodimer, while the minor population was CD4^lowCD8^hi and expressed the CD8ab heterodimer. Phenotypic analysis using different combinations of naïve/memory and activation markers indicated that CD4^hiCD8^low T cells exhibited an effector memory phenotype (CD28^–CD62L^–Fas⁺), were activated (HLA-DR⁺), and proliferated at a higher rate (based on Ki67 expression) than single positive CD4⁺ T cells. Furthermore, they expressed relatively low levels of CD7 and relatively high levels of granzyme B. Real-time PCR analysis revealed lower levels of TCR-rearrangement excisional DNA circles in CD4^hiCD8^low cells than in naïve CD4⁺ T cells. Intracellular cytokine staining indicated that CD4^hiCD8^low cells produced TNF-a and IFN-g in response to stimulation with CMV and that the frequency of CMV-specific cells was enriched in CD4^hiCD8^low cells compared with CD4^hiCD8^– cells.  Cross-sectional studies revealed lower levels of CD4^hiCD8^low T cells in SIV-infected animals compared to uninfected controls, an observation borne out by prospective studies of SIV-infected animals. 

Conclusions:  Taken together, these data suggest that CD4^hiCD8^low T cells represent a distinct population of effector memory CD4+ T cells and that this cell population is depleted during the course of SIV infection.

Keywords: CD4+CD8+ Double positive T cells; SIV