Distinct SIV-specific CD8⁺ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are...

Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8⁺ T cell functions, which requires a deeper understanding of CD8⁺ T cells promoting HIV control. Here we identifiy an antigen-responsive TOX^hiTCF1⁺CD39⁺CD8⁺ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8⁺ T cells and proteomic analysis of purified CD8⁺ T cell subsets identified TOX^hiTCF1⁺CD39⁺CD8⁺ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOX^hiTCF1⁺CD39⁺CD8⁺ T cells were found at higher frequency than TCF1^-CD39⁺CD8⁺ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA⁺ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOX^hiTCF1⁺CD39⁺CD8⁺ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8⁺ T cells contributes to limiting SIV and HIV persistence.