Inadequate T follicular cell help impairs B cell immunity during HIV infection

Cubas, Rafael; Mudd, Joseph C.; Savoye, Anne Laure; Perreau, Matthieu; Grevenynghe, Julien van; Metcalf, Talibah; Connick, Elizabeth; Meditz, Amie L.; Freeman, Gordon J.; Abesada-Terk, Guillermo; Jacobson, Jeffrey M.; Brooks, Ari D.; Crotty, Shane; Estes, Jacob D.; Pantaleo, Giuseppe; Lederman, Michael M.; Haddad, Elias K.

doi:10.1038/nm.3109

Cited by 341 publications

(421 citation statements)

References 40 publications

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“…Taken together, our data demonstrate that certain memory B cell subsets are correlated with Env-specific IL-21 ϩ CXCR5 ϩ CD4 ϩ T cells but not bulk CXCR5 ϩ CD4 ϩ T cells, supporting our previous study showing that IL-21 secretion may better identify pTfh cells (19). Moreover, our partially divergent association in HIV progressors versus controllers suggests a functional impairment of HIV-specific pTfh cells in HIV progressors, in accordance with data for GC Tfh cells (12).…”

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But supporting

confidence: 91%

“…While it has been shown that Tfh cells are expanded during chronic HIV infection (8,11), their ability to help induce maturation and class switching provided to B cells appears to be diminished, in part due to a functional impairment of these cells within the GC (12,13). Similarly, memory B cells have been demonstrated to be phenotypically skewed during chronic HIV infection by direct and bystander activation mechanisms (14,15).…”

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confidence: 99%

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ϩ CD4 ϩ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ϩ CD4 ϩ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ϩ CD4 ϩ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ϩ CD4 ϩ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ϩ CD4 ϩ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

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Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But supporting

confidence: 91%

mentioning

confidence: 99%

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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“…Despite the susceptibility of Tfh cells to infection with SIV/HIV, the frequency of GC Tfh cells begins to increase within a few months of infection188 and elevated Tfh cell numbers are routinely observed in LNs during chronic SIV and HIV infections,168, 173, 189, 190, 191 although Tfh cells are eventually depleted as progression to acquired immunodeficiency syndrome (AIDS) occurs 192. The expansion in Tfh cells is associated with an increase in GC B cells and plasma cells and elevated IgG production, suggesting that Tfh cells contribute to the dysregulation of B cells and antibody production that occurs during HIV‐1 infection 191.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

“…LN GC Tfh cells from chronically HIV‐infected individuals were shown to have an impaired ability to provide help for B cells in in vitro co‐culture assays, with Tfh cell helper capacity correlating negatively with viral load 190. GC B cells from HIV‐1 infected individuals express elevated levels of programmed cell death ligand 1 (PD‐L1), binding of which to PD‐1 on Tfh cells reduced their activation, ICOS expression, and IL‐21 production in vitro, contributing to their poor helper capacity 190. The functional capacity of circulating Tfh cells was also found to be impaired: the proportion of cells producing cytokines including IL‐21 was reduced, and they again exhibited a reduced B‐cell helper capacity in vitro 163.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

“…The functional capacity of circulating Tfh cells was also found to be impaired: the proportion of cells producing cytokines including IL‐21 was reduced, and they again exhibited a reduced B‐cell helper capacity in vitro 163. These defects in Tfh cell function appear to develop very rapidly, during the acute phase of HIV‐1 infection 190, 197. Analysis of both GC Tfh cells in SIV‐infected macaques198 and circulating CXCR3 − CXCR5 + cells in individuals chronically infected with HIV‐1199 suggests that Tfh cells become more Th1‐polarized by chronic infection.…”

Section: T Follicular Helper Cells and Their Role In Bnab Inductionmentioning

confidence: 99%

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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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Follicular Helper T Cells

Chen

2016

Encyclopedia of Life Sciences

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Follicular helper T (Tfh) cells are a subset of helper T cells with specialised functions to support high‐affinity and long‐term antibody responses. Tfh cells express high levels of transcription factor Bcl6, chemokine receptor CXCR5, cytokine IL‐21 and costimulatory receptor PD‐1 and ICOS, showing a phenotype distinct from other helper T‐cell subsets. The differentiation and function of Tfh cells are regulated by a unique molecular program orchestrated by the transcriptional factor Bcl6. The knowledge of Tfh cells provides new insights into the physiopathology of many human diseases, including immunodeficiency, autoimmune disease, infection and cancer. Key Concepts Tfh cells are a helper T‐cell subset. Tfh cells regulate antibody response. CXCR5 is an important functional marker for Tfh cells. The ICOS–Bcl6 pathway critically regulates the differentiation of Tfh cells. Certain primary immunodeficiencies show defects in Tfh cells. Aberrant and/or excessive Tfh function promotes autoimmune diseases.

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Inadequate T follicular cell help impairs B cell immunity during HIV infection

Cited by 341 publications

References 40 publications

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

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

Follicular Helper T Cells

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