Sequential IL-15 and TGF-β1 stimulation expands reprogrammed CD103⁺CD39⁺ effector CD8⁺T cells and enhances HIV control

Abstract

During analytical treatment interruption (ATI), failure to contain tissue HIV reservoirs remains a major barrier to remission. We conditioned peripheral blood mononuclear cells with cues that promote tissue-resident memory differentiation, aiming to reprogram HIV-specific CD8+T cells for these tissue microenvironments. Sequential IL-15/TGF-{beta}1-stimulation expanded proliferative CD103+CD39+ effector populations and restored polyfunctional HIV-specific CD8+T cell responses, irrespective of CD39 or PD-1 expression. Cytokine-stimulated CD8+T cells enhanced ex vivo elimination of the HIV reservoir, and within the induced effector pool, only CD69+ subsets expressing CD103+ or CD39+ eliminated intact HIV-1 genomes. Single-cell transcriptomics showed that IL-15/TGF-{beta}1 stimulation increased clonotypic diversity and expanded resident-like effector clusters with reduced immune-checkpoint receptor expression and augmented mitochondrial function, findings confirmed by flow cytometry. Engrafted recipients from a humanized mouse ATI model more effectively eliminated HIV+-reactivated cells after adoptive transfer of sequentially-treated CD8+T cells. Thus, IL-15/TGF-{beta}1-mediated CD8+T cell reprogramming represents a promising immunotherapy to enable immune control after ATI.