Induction of follicular-like CXCR5⁺ CD8⁺ T Cells by TGF-β1/IL-23 Is Limited during HIV Infection

Follicular CD4⁺ T cells are the main HIV reservoirs due to, among other factors, the low frequency of CD8⁺ T cells in lymphoid follicles. Follicular CXCR5⁺ CD8⁺ T cells are associated with HIV control, but their differentiation conditions are yet undefined. In this study, we explored the in vitro effect of transforming growth factor (TGF)-β1, interleukin (IL)-12, and IL-23 on the induction of CXCR5, the follicle homing receptor, in human circulating CD8⁺ T cells from seronegative, and treated HIV-infected individuals. The combination of TGF-β1 plus IL-23 induced the highest expression of CXCR5 in purified CD8⁺ T cells. These CXCR5⁺ CD8⁺ T cells also expressed a transcriptional and phenotypic profile similar to that of follicular CD4⁺ T cells, such as the upregulation of BCL6, inducible costimulator and CD40L, and downregulation of PRDM1. These cells responded in vitro to CXCL13 and had low expression of CCR7. In addition, after polyclonal stimulation, they produced IL-21, interferon-γ, and de novo perforin. However, in comparison with seronegative individuals, CD8⁺ T cells from HIV-infected patients had a lower response to TGF-β1/IL-23, a defect that was restored with the blockade of the programmed cell death 1 inhibitory receptor. Thus, TGF-β1 plus IL-23 induce follicular-like CXCR5⁺ CD8⁺ T cells in seronegative individuals, but in HIV-infected patients there is a limited response which could impair the generation of this cell population.