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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 4

CXCR3+PD-1lo pTfh cells support B cell activation and differentiation.

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CXCR3+PD-1lo pTfh cells support B cell activation and differentiation.
(...
(A) Dot plots reflect CXCR5 versus PD-1 expression on sorted CXCR3+ and CXCR3– PD-1lo and PD-1hi pTfh cells on day 6 in coculture with autologous total B cells in the presence of SEB in a representative experiment. Numbers above the gates represent percentages of cells. (B and C) Proportions of PD-1hi (B) and PD-1lo (C) CD4 T cells after 6-day culture of isolated CXCR3+PD-1lo (n = 5), CXCR3+PD-1hi (n = 5), CXCR3–PD-1lo (n = 4), and CXCR3–PD-1hi (n = 5) cells with autologous B cells and SEB. (D) Representative flow cytometry analysis showing CD38 vs CD27 surface expression on gated CD19+ B cells on day 6 of coculture with SEB alone or the indicated pTfh populations. Numbers within the gates represent percentages of cells. (E) Proportions of CD38intCD27int activated memory and CD38hiCD27hi plasmablast-like (PB-like) B cells on day 6 of coculture with the indicated pTfh populations. CXCR3+PD-1lo (n = 5), CXCR3+PD-1hi (n = 5), CXCR3–PD-1lo (n = 4), and CXCR3–PD-1hi (n = 5). Differences between each condition with indicated pTfh subset and control B cells activated with SEB alone were tested for statistical significance using a Kruskal-Wallis test followed by Dunn’s test (*P < 0.05). (F and G) Luminex analysis of the indicated cytokine (F) and Ig (G) concentrations present in supernatants on day 6 in the indicated cocultures with CXCR3+PD-1lo (n = 5) CXCR3+PD-1hi (n = 5), CXCR3–PD-1lo (n = 4), and CXCR3–PD-1hi (n = 5) pTfh cells. Statistical significance was calculated using a Kruskal-Wallis test followed by a Dunn’s test (**P < 0.01).

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