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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 5

Characterization of memory cell subsets within Tfh-like cells.

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Characterization of memory cell subsets within Tfh-like cells.
(A and B)...
(A and B) Representative flow cytometry analysis of memory cell subsets in total CD4+ T cells (A) and in PD-1lo and PD-1hi CXCR5+CXCR3+ and CXCR5+CXCR3– pTfh cells (B). CCR7 versus CD45RO expression defines central memory (CM), effector memory (EM), terminally differentiated (TD) and naive-like (NA-like) T cells (upper panels). NA-like T cells are subdivided into memory stem cells (SCM) and naive (NA) cells based on expression levels of CD95 (lower panels). (C and D) Proportions of memory subsets within PD-1lo and PD-1hi CXCR3+ and CXCR3– cells, and total CD4+ T cells (CD4) from peripheral blood (P. Blood; upper panel, n = 7), tonsils (middle panel, n = 8), and lymph nodes (lower panel, n = 7) (C). Proportions of T memory stem cells (SCM) within each pTfh subset from the indicated compartments are represented separately in D. Statistical significance within individual subset (C) and in TSCM proportions across different subsets (D) was calculated using a Friedman test followed by a Dunn’s test (*P < 0.05; **P < 0.01; ***P < 0.001).

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