A favorable follicular helper CD4+ T cell programming characterizes neutralization activity in chronic HIV infection
Eirini Moysi, Ashish A. Sharma, Sijy O’Dell, Spiros Georgakis, Perla Mariana Del Rio Estrada, Ghneim Khader, Alonso Arana, Fernanda Torres-Ruiz, Mauricio González Navarro, Yara Andrea Luna Villalobos, Santiago Avila Rios, Gustavo Reyes-Teran, Margaret H. Beddall, Sung Hee Ko, Frida Belinky, Michail Orfanakis, Laurence de Leval, Ana B. Enriquez, Clarisa M. Buckner, Susan Moir, Helen Lindsay, Raphael Gottardo, Nicole Doria-Rose, Eli A. Boritz, John R. Mascola, Rafick-Pierre Sekaly, Richard A. Koup, Constantinos Petrovas
Eirini Moysi, Ashish A. Sharma, Sijy O’Dell, Spiros Georgakis, Perla Mariana Del Rio Estrada, Ghneim Khader, Alonso Arana, Fernanda Torres-Ruiz, Mauricio González Navarro, Yara Andrea Luna Villalobos, Santiago Avila Rios, Gustavo Reyes-Teran, Margaret H. Beddall, Sung Hee Ko, Frida Belinky, Michail Orfanakis, Laurence de Leval, Ana B. Enriquez, Clarisa M. Buckner, Susan Moir, Helen Lindsay, Raphael Gottardo, Nicole Doria-Rose, Eli A. Boritz, John R. Mascola, Rafick-Pierre Sekaly, Richard A. Koup, Constantinos Petrovas
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Research Article AIDS/HIV Immunology

A favorable follicular helper CD4+ T cell programming characterizes neutralization activity in chronic HIV infection

Abstract

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these Abs are poorly understood. Here, we explored LN-associated histological, immunological, and virological determinants of bNAb generation in a cohort of antiretroviral therapy–naive PLWH. We found that participants who produce bNAbs, termed “neutralizers” (Ns), have a better-preserved LN-associated B cell follicle architecture than do PLWH who do not. The former was associated with a substantially higher in situ prevalence of B-cell lymphoma 6 (Bcl-6hi) follicular helper CD4+ T cells (Tfh), expressing a molecular program that favors their differentiation and stemness, and substantially reduced IL-10 follicular suppressor CD4+ T cells. Furthermore, our data reveal possible molecular targets mediating Tfh–B cell interactions in Ns. Together, we identify germinal center cellular and molecular signatures that could contribute to the development of bNAbs in PLWH.

Authors

Eirini Moysi, Ashish A. Sharma, Sijy O’Dell, Spiros Georgakis, Perla Mariana Del Rio Estrada, Ghneim Khader, Alonso Arana, Fernanda Torres-Ruiz, Mauricio González Navarro, Yara Andrea Luna Villalobos, Santiago Avila Rios, Gustavo Reyes-Teran, Margaret H. Beddall, Sung Hee Ko, Frida Belinky, Michail Orfanakis, Laurence de Leval, Ana B. Enriquez, Clarisa M. Buckner, Susan Moir, Helen Lindsay, Raphael Gottardo, Nicole Doria-Rose, Eli A. Boritz, John R. Mascola, Rafick-Pierre Sekaly, Richard A. Koup, Constantinos Petrovas

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Figure 5

GC B cells express a molecular profile favoring GC development in cross-neutralization LNs.

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GC B cells express a molecular profile favoring GC development in cross-...
(A) Representative confocal images showing the distribution of BCL-6 (yellow) and Ki67 (magenta) within the GCs of NNs and Ns. Original magnification, ×40 with 1% zoom; scale bars: 100 μm. Superplots show normalized CD20hi and Bcl-6hiKi67hiCD20hi B cell numbers of both individual (faint background symbols) and mean ± SEM (bold foreground symbols) follicular measurements in NNs (n = 6, blue) versus Ns (n = 6, red), as measured by quantitative imaging analysis and histocytometry. The different symbols represent different donors. For statistical comparisons using mean measurements, a Mann-Whitney U test was applied (P = 0.588, P = 0.2403). (B) UMAP projections of B cell populations identified by scRNA analysis in total l ymph node mononuclear cells, color-coded by B cell category. (C) Volcano plots and dot plots of DEGs and NESs from GSEA for selection of B cell–specific ligands and transcription factors. The DEGs were calculated using the MAST (Hurdle model–based) test via the FindMarkers function using the Seurat package in R. P values were corrected using the Benjamini-Hochberg method and genes meeting an adjusted *P < 0.05 and (log2FC) > 0.5 are highlighted on the volcano plot. Dots in the volcano plots represent genes that were significantly downregulated (blue) or upregulated (red) in Ns. (D) Heatmap of pairwise Tfh–GC B cell interactions as identified through ligand-target analysis. Darker colors denote interactions corresponding to an increased regulatory potential.