Induction of Follicular-Like CXCR5 ⁺ CD8 ⁺ T Cells by TGF- β 1/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)- β 1, 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- β 1 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- β 1/IL-23, a defect that was restored with the blockade of the programmed cell death 1 inhibitory receptor. Thus, TGF- β 1 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.