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

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Abstract

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.

Authors

Enrique Martin-Gayo, Jacqueline Cronin, Taylor Hickman, Zhengyu Ouyang, Madelene Lindqvist, Kellie E. Kolb, Julian Schulze zur Wiesch, Rafael Cubas, Filippos Porichis, Alex K. Shalek, Jan van Lunzen, Elias K. Haddad, Bruce D. Walker, Daniel E. Kaufmann, Mathias Lichterfeld, Xu G. Yu