Regulatory and Helper Follicular T Cells and Antibody Avidity to Simian Immunodeficiency Virus Glycoprotein 120

Blackburn, Matthew; Ma, Zhien; Caccuri, Francesca; McKinnon, Katherine; Schifanella, Luca; Guan, Yongjun; Gorini, Giacomo; Venzon, David; Fenizia, Claudio; Binello, Nicolò; Gordon, Shari N.; Miller, Christopher J.; Franchini, Genoveffa; Vaccari, Monica

doi:10.4049/jimmunol.1402699

Cited by 32 publications

(51 citation statements)

References 66 publications

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“…The frequency of Tfr cells within total LN CD4 + T cells does not appear to be increased during chronic SIV282, 283 or HIV‐1 infection,284 although the absolute number of Tfr cells is increased. One report suggests that the Tfr cell frequency in the spleen may be increased during HIV‐1 infection, however 285.…”

Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 92%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 92%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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“…T follicular regulatory cells (T FR ) are a subset of follicular cells that directly regulate numbers and function of T FH during HIV and SIV infection [31–34]. Two studies linked relative decreases of T FR to expansions of T FH in the SIV-infected rhesus macaque model [31, 32]. Increased cell survival may contribute to the persistence of T FH as well.…”

Section: Role Of Tfh In Hiv Replication In Untreated Diseasementioning

confidence: 99%

T FH in HIV Latency and as Sources of Replication-Competent Virus

Brodie

Connick

2016

Trends in Microbiology

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During untreated disease, HIV replication is concentrated within T follicular helper cells (TFH). Heightened permissiveness, the presence of highly infectious virions on follicular dendritic cells (FDC), low frequencies of virus-specific cytotoxic T lymphocytes (CTL) in B cell follicles, expansions in TFH, and TFH dysfunction all likely promote replication in TFH. Limited data suggest that memory TFH play a role in the latent or subclinical reservoir of HIV during antiretroviral therapy (ART), potentially for many of the same reasons. A better understanding of the role of memory TFH and FDC-bound virions in promoting recrudescent viremia in the setting of ART cessation is essential. Studies that target follicular virus reservoirs are needed to determine their role in HIV latency and to suggest successful cure strategies.

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“…Although several studies have phenotypically and functionally characterized the total population of macaque T FH cells in naïve and SIV-infected animals (23, 27-31), quantification of vaccine-induced SIV-specific IL-21-producing macaque T FH cells has not yet been reported. In order to better understand the development of humoral immune responses and the contribution of T FH to protective efficacy, in the present study we have identified and quantified SIV-specific LN-resident IL-21 + T FH cells for the first time in a pre-clinical non-human primate vaccine trial.…”

Section: Introductionmentioning

confidence: 99%

Vaccine Induction of Lymph Node–Resident Simian Immunodeficiency Virus Env-Specific T Follicular Helper Cells in Rhesus Macaques

Vargas-Inchaustegui

Demers

Shaw

et al. 2016

The Journal of Immunology

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Measurement of antigen-specific T follicular helper (TFH) cell activity in rhesus macaques has not previously been reported. Given that rhesus macaques are the animal model of choice for evaluating protective efficacy of HIV/SIV vaccine candidates and that TFH cells play a pivotal role in aiding B cell maturation, quantifying vaccine-induction of HIV/SIV-specific TFH cells would greatly benefit vaccine-development. Here we quantified SIV Env-specific IL-21-producing TFH cells for the first time in a non-human primate vaccine study. Macaques were primed twice mucosally with Adenovirus 5 host range mutant (Ad5hr) recombinants encoding SIV Env, Rev, Gag and Nef followed by two intramuscular boosts with monomeric SIV gp120 or oligomeric SIV gp140 proteins. Two weeks after the second protein boost we obtained lymph node biopsies and quantified the frequency of total and SIV Env-specific IL-21+ TFH cells and total germinal center (GC) B cells, the size and number of GCs, and the frequency of SIV-specific antibody secreting cells in B cell zones. Multiple correlation analyses established the importance of TFH for development of B cell responses in systemic and mucosally localized compartments including blood, bone marrow, and rectum. Our results suggest that the SIV-specific TFH cells, initially induced by replicating Ad-recombinant priming, are long-lived. The multiple correlations of SIV Env-specific TFH cells with systemic and mucosal SIV-specific B cell responses indicate that this cell population should be further investigated in HIV vaccine development as a novel correlate of immunity.

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Regulatory and Helper Follicular T Cells and Antibody Avidity to Simian Immunodeficiency Virus Glycoprotein 120

Cited by 32 publications

References 66 publications

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

T FH in HIV Latency and as Sources of Replication-Competent Virus

Vaccine Induction of Lymph Node–Resident Simian Immunodeficiency Virus Env-Specific T Follicular Helper Cells in Rhesus Macaques

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