Induction of Follicular-Like CXCR5 ⁺ CD8 ⁺ T Cells by TGF- <i>β</i> 1/IL-23 Is Limited During HIV Infection

Abstract

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 <i>in vitro</i> effect of transforming growth factor (TGF)-<i>β</i>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-<i>β</i>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 <i>BCL6</i>, inducible costimulator and CD40L, and downregulation of <i>PRDM1</i>. These cells responded <i>in vitro</i> to CXCL13 and had low expression of CCR7. In addition, after polyclonal stimulation, they produced IL-21, interferon-<i>γ</i>, and <i>de novo</i> perforin. However, in comparison with seronegative individuals, CD8⁺ T cells from HIV-infected patients had a lower response to TGF-<i>β</i>1/IL-23, a defect that was restored with the blockade of the programmed cell death 1 inhibitory receptor. Thus, TGF-<i>β</i>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.