Lymph-Node-Based CD3 + CD20 + Cells Emerge from Membrane Exchange between T Follicular Helper Cells and B Cells and Increase Their Frequency following Simian Immunodeficiency Virus Infection

• Published in: Journal of virology Vol. 97; no. 6; p. e0176022
• Main Authors: Samer, Sadia, Chowdhury, Ankita, Wiche Salinas, Tomas Raul, Estrada, Perla M Del Rio, Reuter, Morgan, Tharp, Gregory, Bosinger, Steven, Cervasi, Barbara, Auger, James, Gill, Kiran, Ablanedo-Terrazas, Yuria, Reyes-Teran, Gustavo, Estes, Jacob D, Betts, Michael R, Silvestri, Guido, Paiardini, Mirko
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 29.06.2023
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - virology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD40 Ligand - genetics; DNA, Viral - metabolism; Gene Expression - immunology; HIV Infections - immunology; HIV Infections - virology; Humans; Immunology; Lymph Nodes - cytology; Lymphoid Tissue - cytology; Lymphoid Tissue - immunology; Lymphoid Tissue - virology; Macaca mulatta; Pathogenesis and Immunity; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - genetics; T Follicular Helper Cells - immunology; T Follicular Helper Cells - virology; CD3+ CD20+ cells; nonhuman primates; SIV infection; HIV infection; TFH; lymphoid tissues
• ISSN: 0022-538X; 1098-5514; 1098-5514
• DOI: 10.1128/jvi.01760-22

CD4 T follicular helper (T ) cells are key targets for human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication and contribute to the virus reservoir under antiretroviral therapy (ART). Here, we describe a novel CD3 CD20 double-positive (DP) lymphocyte subset, resident in secondary lymphoid organs of humans and rhesus macaques (RMs), that appear predominantly after membrane exchange between T and B cells. DP lymphocytes are enriched in cells displaying a T phenotype (CD4 PD1 CXCR5 ), function (interleukin 21 positive [IL-21 ]), and gene expression profile. Importantly, expression of CD40L upon brief mitogen stimulation identifies, by specific gene-expression signatures, DP cells of T -cell origin versus those of B-cell origin. Analysis of 56 RMs showed that DP cells (i) significantly increase following SIV infection, (ii) are reduced after 12 months of ART in comparison to pre-ART levels, and (iii) expand to a significantly higher frequency following ART interruption. Quantification of total SIV-gag DNA on sorted DP cells from chronically infected RMs showed that these cells are susceptible to SIV infection. These data reinforce earlier observations that CD20 T cells are infected and expanded by HIV infection, while suggesting that these cells phenotypically overlap activated CD4 T cells that acquire CD20 expression via trogocytosis and can be targeted as part of therapeutic strategies aimed at HIV remission. The HIV reservoir is largely composed of latently infected memory CD4 T cells that persist during antiretroviral therapy and constitute a major barrier toward HIV eradication. In particular, CD4 T follicular helper cells have been demonstrated as key targets for viral replication and persistence under ART. In lymph nodes from HIV-infected humans and SIV-infected rhesus macaques, we show that CD3 CD20 lymphocytes emerge after membrane exchange between T cells and B cells and are enriched in phenotypic, functional, and gene expression profiles found in T follicular helper cells. Furthermore, in SIV-infected rhesus macaques, these cells expand following experimental infection and after interruption of ART and harbor SIV DNA at levels similar to those found in CD4 T cells; thus, CD3 CD20 lymphocytes are susceptible to SIV infection and can contribute to SIV persistence.