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Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth
Enrique Martin-Gayo, … , Mathias Lichterfeld, Xu G. Yu
Enrique Martin-Gayo, … , Mathias Lichterfeld, Xu G. Yu
Published January 26, 2017
Citation Information: JCI Insight. 2017;2(2):e89574. https://doi.org/10.1172/jci.insight.89574.
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Research Article AIDS/HIV

Circulating CXCR5+CXCR3+PD-1lo 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-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.

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

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Figure 1

CXCR5+CXCR3+PD-1lo Tfh-like cells are enriched in controller neutralizers and associated with neutralizing breadth against HIV-1.

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CXCR5+CXCR3+PD-1lo Tfh-like cells are enriched in controller neutralizer...
(A) Proportions of total CXCR3+PD-1+CXCR5+ or CXCR3–PD-1+CXCR5+ subpopulations within total CD4+ T cells in blood from HIV-1–infected controller non-neutralizers (NN, n = 20) and neutralizers (NT, n = 25). Statistical differences were calculated using a Wilcoxon matched-pairs test in each group of patients (**P < 0.01). (B) Proportions of PD-1lo or PD-1hi cells within CXCR3+CXCR5+ and CXCR3–CXCR5+ CD4+ T cell populations from the indicated study cohorts. Statistical differences between NN and NT were calculated separately for each individual pTfh subset using a Mann Whitney U test (*P < 0.05). (C) Spearman correlations between ratios of PD-1lo vs PD-1hi cells within CXCR3+ (left) and CXCR3– (right) CXCR5+ CD4+ T cells from controller neutralizers and the corresponding breadth of HIV-1–specific neutralizing antibodies. Numbers included in the top right corner of each plot reflect nominal P values and Spearman r values.

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ISSN 2379-3708

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