Increased levels of Foxp3+CD4+NKT-like cells are associated with HIV disease progression.

Persistent immune activation is a key factor contributing to AIDS progression and non-AIDS-associated complications. NKT-like cells were found to exert immunosuppressive roles under some pathological situations by Foxp3 upregulation. Here, we found that Foxp3 was mainly expressed on CD4+NKT-like cells in untreated people living with HIV (PLWH) and the frequencies of Foxp3+CD4+NKT-like cells were correlated with HIV disease progression. Furthermore, the percentage of Foxp3+CD4+NKT-like cells was positively associated with immune activation and systematic inflammation. Foxp3+CD4+NKT-like cells might exert immunomodulatory effects by elevating the expression of TGF-β, IL-10, CD39, CD25, GITR, Ki67 and TIGIT. However, our analyses further identified Foxp3+CD4+NKT-like cells as a distinct subset that differed from conventional regulatory T cells. Notably, patients with higher baseline levels of Foxp3+CD4+NKT-like cells had a greater risk of poor immune reconstitution. These findings emphasized the importance of Foxp3+CD4+NKT-like cells during HIV infection and revealed its predictive role in immune reconstitution.