Circulating CXCR5⁺CXCR3⁺PD-1^lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

HIV-1-specific broadly neutralizing antibodies (bnAbs) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5⁺CXCR3⁺PD-1^lo CD4⁺ T cells. These CXCR3⁺PD-1^lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3⁺PD-1^lo Tfh-like cells contained higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1^hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5⁺CXCR3⁺PD-1^lo cells represent a dendritic cell-primed precursor cell population for PD-1^hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia.