Circulating CXCR5+CXCR3+PD-1lo Tfh-like Cells in HIV-1 Controllers with Neutralizing Antibody Breadth

Biology Biology
Immunology Immunology
Infectious Disease Infectious Disease
Alex K. Shalek Alex K. Shalek
Kellie Kolb Kellie Kolb

Martin-Gayo et al.▾ Martin-Gayo, E., Cronin, J., Hickman, T., Ouyang, Z., Lindqvist, M., Kolb, K.E., Schulze zur Wiesch, J., Cubas, R., Porichis, F., Shalek, A.K., van Lunzen, J., Haddad, E.K., Walker, B.D., Kaufmann, D.E., Lichterfeld, M., Yu, X.G.

JCI Insight , Volume 2

January, 2017


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-1lo CD4+ T cells. These CXCR3+PD-1lo 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-1lo Tfh-like cells contained higher proportions of stem cell–like memory T cells, and upon antigenic stimulation differentiated into PD-1hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+CXCR3+PD-1lo cells represent a dendritic cell–primed precursor cell population for PD-1hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high-level viremia.