Potent HIV-specific responses are enriched in a unique subset of CD8 ⁺ T cells that coexpresses CD4 on its surface

In humans, approximately 3% of peripheral CD8⁺ T cells coexpress CD4 dimly on their surface and hence are designated as CD4 ^dimCD8^bright T cells. We evaluated the contribution of this CD4^dimCD8^bright T-cell population to anti-HIV immunity.We demonstrate that CD4^dimCD8^bright T cells generate greater than 55% of CD8⁺ T-cell antigen recognition and effector response to HIV, as evaluated by multiple parameters for assessing T-cell antiviral immunity, including HIV tetramer recognition, cytokine production, and cytolytic potential. Inhibition of major histocompatibility class II (MHC-II) on target cells or CD4 on CD4^dimCD8 ^bright T cells diminishes their anti-HIV responses, suggesting that CD4 on effector cells and MHC-II on target cells provides an additional arm of contact between effector and target cells which is critical to CD4 ^dimCD8^bright T-cell function. CD4^dimCD8 ^bright T cells also exhibit features that are indicative of central memory T cells. Finally, CD4^dimCD8^bright T cells are elevated in blood of HIV⁺ long-term nonprogressors in comparison to HIV⁺ donors. Collectively, our findings show that CD4 ^dimCD8^bright T cells designate an enriched antiviral subpopulation of CD8⁺ T cells that should be targeted for therapeutic intervention or evaluation of vaccine efficacy.