HIV-Specific CD8⁺ T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue

Elimination of lymphoid tissue reservoirs is a key component of HIV eradication strategies. CD8⁺ T cells play a critical role in control of HIV, but their functional attributes in lymph nodes (LNs) remain unclear. Here, we show that memory, follicular CXCR5⁺, and HIV-specific CD8⁺ T cells from LNs do not manifest the properties of cytolytic CD8⁺ T cells. While the frequency of follicular CXCR5⁺ CD8⁺ T cells was strongly inversely associated with peripheral viremia, this association was not dependent on cytolytic CXCR5⁺ CD8⁺ T cells. Moreover, the poor cytolytic activity of LN CD8⁺ T cells was linked to a compartmentalized dissociation between effector programming and the transcription factor T-bet. In line with this, activation of LN CD8⁺ T cells only partially induced the acquisition of cytolytic functions relative to peripheral blood CD8⁺ T cells. These results suggest that a state of immune privilege against CD8⁺ T cell-mediated cytolysis exists in lymphoid tissue, potentially facilitating the persistence of HIV.