Frequencies of lymphoid T‐follicular helper cells obtained longitudinally by lymph node fine‐needle aspiration correlate significantly with viral load in <scp>SIV</scp>‐infected rhesus monkeys

Klippert, Antonina; Stolte-Leeb, Nicole; Neumann, Berit; Sauermann, Ulrike; Daskalaki, Maria; Gawanbacht, Ali; Kirchhoff, Frank; Stahl–Hennig∥, Christiane

doi:10.1111/jmp.12186

Cited by 6 publications

(12 citation statements)

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“…Inguinal LNs were obtained following booster immunizations administered to the thigh. We biopsied whole LNs rather than using sequential sampling with the fine-needle aspiration technique, which has been applied in longitudinal assessments of LN cell subsets in HIV-1 patients and macaques (60)(61)(62)(63). T FH cell evaluation using this method may be problematic, as the needle may withdraw cells from either the T or B cell zone of the LN (64).…”

Section: Discussionmentioning

confidence: 99%

Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques

Hait

Vargas-Inchaustegui

Musich

et al. 2019

J Virol

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T follicular helper (TFH) cells are fundamental in germinal center (GC) maturation and selection of antigen-specific B cells within secondary lymphoid organs. GC-resident TFH cells have been fully characterized in human immunodeficiency virus (HIV) infection. However, the role of GC TFH cells in GC B cell responses following various simian immunodeficiency virus (SIV) vaccine regimens in rhesus macaques (RMs) has not been fully investigated. We characterized GC TFH cells of RMs over the course of a mucosal/systemic vaccination regimen to elucidate GC formation and SIV humoral response generation. Animals were mucosally primed twice with replicating adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants and systemically boosted with ALVAC-SIVM766Gag/Pro/gp120-TM and SIVM766&CG7V gD-gp120 proteins formulated in alum hydroxide (ALVAC/Env) or DNA encoding SIVenv/SIVGag/rhesus interleukin 12 (IL-12) plus SIVM766&CG7V gD-gp120 proteins formulated in alum phosphate (DNA&Env). Lymph nodes were biopsied in macaque subgroups prevaccination and at day 3, 7, or 14 after the 2nd Ad5hr-SIV prime and the 2nd vector/Env boost. Evaluations of GC TFH and GC B cell dynamics including correlation analyses supported a significant role for early GC TFH cells in providing B cell help during initial phases of GC formation. GC TFH responses at day 3 post-mucosal priming were consistent with generation of Env-specific memory B cells in GCs and elicitation of prolonged Env-specific humoral immunity in the rectal mucosa. GC Env-specific memory B cell responses elicited early post-systemic boosting correlated significantly with decreased viremia postinfection. Our results highlight the importance of early GC TFH cell responses for robust GC maturation and generation of long-lasting SIV-specific humoral responses at mucosal and systemic sites. Further investigation of GC TFH cell dynamics should facilitate development of an efficacious HIV vaccine. IMPORTANCE The modest HIV protection observed in the human RV144 vaccine trial associated antibody responses with vaccine efficacy. T follicular helper (TFH) cells are CD4+ T cells that select antibody secreting cells with high antigenic affinity in germinal centers (GCs) within secondary lymphoid organs. To evaluate the role of TFH cells in eliciting prolonged virus-specific humoral responses, we vaccinated rhesus macaques with a combined mucosal prime/systemic boost regimen followed by repeated low-dose intrarectal challenges with SIV, mimicking human exposure to HIV-1. Although the vaccine regimen did not prevent SIV infection, decreased viremia was observed in the immunized macaques. Importantly, vaccine-induced TFH responses elicited at day 3 postimmunization and robust GC maturation were strongly associated. Further, early TFH-dependent SIV-specific B cell responses were also correlated with decreased viremia. Our findings highlight the contribution of early vaccine-induced GC TFH responses to elicitation of SIV-specific humoral immunity and implicate their participation in SIV control.

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Section: Discussionmentioning

confidence: 99%

Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques

Hait

Vargas-Inchaustegui

Musich

et al. 2019

J Virol

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“…While in macaques it is possible to surgically remove the draining LNs at different time points after an immunization or an experimental infection, this procedure is invasive and may disrupt ongoing immune responses. Two studies have used fine-needle aspirations (FNAs) technique to collect cells from LNs of pigtail and rhesus macaques ( 50 , 51 ). In both models, T FH cell where readably measurable, suggesting that FNA may be an interesting alternative to collect small numbers of GC cells for further analyses, while maintaining ongoing immune responses.…”

Section: Introductionmentioning

confidence: 99%

T Cell Subsets in the Germinal Center: Lessons from the Macaque Model

Vaccari

Franchini

2018

Front. Immunol.

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Germinal centers (GCs) are organized lymphoid tissue microstructures where B cells proliferate and differentiate into memory B cells and plasma cells. A few distinctive subsets of highly specialized T cells gain access to the GCs by expressing the B cell zone–homing C-X-C chemokine receptor type 5 (CXCR5) while losing the T cell zone–homing chemokine receptor CCR7. Help from T cells is critical to induce B cell proliferation and somatic hyper mutation and to limit GC reactions. CD4+ T follicular helper (TFH) cells required for the formation of GCs and for the generation of long-lived, high-affinity B cells. Regulatory CD4+ (TFR) and CD8+ T cells co-localize with TFH cells and keep their expansion in check, thus limiting GC reactions. A cytotoxic CXCR5pos CD8+ T cell subset has been described in GCs in humans: although low in number, GC CD8+ T cells can expand rapidly during certain viral infections. Because these subsets find their home in secondary lymphoid tissues (lymph nodes and spleen) that are difficult to obtain in humans, GC–homing T cells have been extensively studied in mice. Nevertheless, significant limitations in using this model, such as evolutionary divergences between mice and humans and the lack of an optimal mouse model for certain human diseases, have prompted investigators to characterize GC–homing T cells in macaques instead. This review will focus on discoveries made in macaques, particularly in the non-human primate models of simian immunodeficiency virus and simian–human immunodeficiency virus infection. Indeed, experimental studies in these models have allowed researchers to gain insight into the relative role of follicular T cell subsets in HIV progression, virus persistence, and specific B cell responses induced by HIV vaccines. These discoveries have prompted the testing of novel approaches aimed to manipulate follicular T cells to increase the efficacy of HIV vaccines and to eliminate HIV reservoirs.

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“…RNA extraction from cb was performed with peqGOLD TriFast, according to the manufacturer's instructions. Plasma and colon viral RNA levels were quantified by real‐time RT‐PCR assay as previously described .…”

Section: Methodsmentioning

confidence: 99%

Long‐term efficient control of SIV infection in macaques is associated with an intact intestinal barrier

Daskalaki

Neumann

Klippert

et al. 2017

J of Medical Primatology

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Frequencies of lymphoid T‐follicular helper cells obtained longitudinally by lymph node fine‐needle aspiration correlate significantly with viral load in SIV‐infected rhesus monkeys

Abstract: By applying LN-FNA, we showed that T(FH) cell expansion in chronic SIV infection is associated with viral load.

Cited by 6 publications

References 38 publications

Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques

Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques

T Cell Subsets in the Germinal Center: Lessons from the Macaque Model

Long‐term efficient control of SIV infection in macaques is associated with an intact intestinal barrier

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