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

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 2

Primary mDCs from controller neutralizers efficiently induce Tfh-like cells in vitro.

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Primary mDCs from controller neutralizers efficiently induce Tfh-like ce...
(A) Flow cytometry analysis of CXCR5 and PD-1 expression on naive CD4+ T cells from an HIV-1–negative donor cultured for 7 days in the presence of media alone (left) or autologous naive B cells in the absence (middle) or the presence (right) of allogeneic mDCs isolated from an additional HIV-1–negative donor. Rectangles highlight CXCR5+ CD4+ T cells expressing either low or high levels of PD-1 (PD-1Lo and PD-1Hi, respectively). Dot plots from a representative experiment are shown. (B) Intracellular Bcl-6 expression in the indicated CD4+ T cell subsets after coculture with mDCs for 7 days. Left panel shows dot plots from one representative experiment. Right panel shows cumulative mean fluorescence intensity of Bcl-6 data from n = 15 HIV-1–negative study subjects. Statistical significance was calculated using a Friedman test followed by Dunn’s test (**P < 0.01; ***P < 0.001). (C) Proportions of PD-1hi (left) and PD-1lo (right) CXCR5+ CD4+ T cells differentiated from naive CD4+ T cells after 7 days of culture in the presence of autologous naive B cells (–) alone or in combination with allogeneic mDCs from HIV-1–negative donors (NG; n = 16), controller non-neutralizers (NN; n=16), neutralizers (NT; n = 20), untreated (CP; n = 14) and HAART-treated (H; n = 14) chronic progressors. Statistical significance between mDCs from neutralizers and other conditions was calculated using a Kruskal-Wallis test followed by a Dunn’s test (*P < 0.05; ***P < 0.001). (D) Ratios of PD-1lo versus PD-1hi CXCR5+ CD4+ T cells differentiated in the presence of allogeneic mDCs from different study cohorts. Statistical significance between mDCs from NT versus other conditions was calculated using a Kruskal-Wallis test followed by a Dunn’s test (**P < 0.01).