Follicular regulatory T cells produce neuritin to regulate B cells

González-Figueroa, Paula; Roco, Jonathan A.; Papa, Ilenia; Villacís, Lorena Núñez; Stanley, Maurice; Linterman, Michelle A.; Dent, Alexander L.; Cañete, Pablo F.; Vinuesa, Carola G.

doi:10.1016/j.cell.2021.02.027

Cited by 117 publications

(122 citation statements)

References 65 publications

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“…Therefore, understanding the impact of the IgG1 GC B cell checkpoint in the context of health, or its release in disease or during clinical intervention remains an important implication of our current studies. PD-1 is highly expressed on sub-populations of CD4 TFH (Ansel et al, 1999;Fazilleau et al, 2009;Vinuesa et al, 2005) and TFR cells responsible for the proliferation and differentiation of class-switched B cells (Gonzalez-Figueroa et al, 2021;Linterman et al, 2011;Wu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The selective targeting of PD-1 blockade to the IgG1 B cell response provides one clear example of isotype-specific CD4 T cell immune regulation (Higgins et al, 2019;McHeyzer-Williams et al, 2012). We and others have proposed that TFH (Gowthaman et al, 2019;Zhang et al, 2020) and potentially TFR function (Gonzalez-Figueroa et al, 2021;Vinuesa et al, 2016) is organized and delivered in an isotype-specific manner. We have demonstrated the IgG2a-selective memory B cell requirement for T-bet expression, not only for class-switch, but also for survival into memory and re-expansion at antigen recall (Wang et al, 2012) and attribute this requirement to differential memory TFH organization.…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 checkpoint blockade is a highly effective immune therapeutic that re-activates exhausted CD8 T cells during persistent infection (Barber et al, 2006;Hashimoto et al, 2018) and across a variety of cancers (Sharma et al, 2021;Wei et al, 2017). Despite their nonexhausted state, TFH cells (Ansel et al, 1999;Fazilleau et al, 2009;Vinuesa et al, 2005) and their follicular regulatory counterpart (TFR) (Gonzalez-Figueroa et al, 2021;Linterman et al, 2011;Wu et al, 2020) both express PD-1 with highest levels on GC localized subsets (Haynes et al, 2007;Shulman et al, 2013). Genetic ablation of PD-1 results in increased TFH and TFR cell expansion following immunization (Good-Jacobson et al, 2010;Hams et al, 2011;Sage et al, 2013), in the gut (Kawamoto et al, 2012) and in autoimmune models (Nishimura et al, 1999;Nishimura et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

Shuparski

et al. 2021

Preprint

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Adaptive B cell immunity to environmental antigens must be regulated by multiple CD4 T cell dependent tolerance mechanisms. Using integrated single cell strategies, we demonstrate that acute PD-1 blockade induces extensive and selective local anti-inflammatory IgG1 plasma cell (PC) differentiation. Expansion of pre-existing IgG1 germinal center (GC) B cell and enhanced GC programming without memory B cell involvement reveals an isotype-specific GC checkpoint that blocks steady-state IgG1 antibody maturation. While there was no adjuvant impact on immunization, acute PD-1 checkpoint blockade exaggerates anti-commensal IgG1 antibody production, alters microbiome composition and exerts its action in a CD4 T cell dependent manner. These findings reveal a PD-1 controlled adaptive B cell tolerance checkpoint that selectively constrains maturation of pre-existing anti-inflammatory antibodies to prevent over-reaction to steady-state foreign antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

Shuparski

et al. 2021

Preprint

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“…Protein immunization also revealed autoreactive IgG and IgE in the serum of mice lacking Tfr cells ( 43 ). Tfr-deficient mice also spontaneously develop autoantibodies at older age ( 44 , 45 ). The mode of action by which Tfr cells maintain tolerance is incompletely understood, with CTLA-4 being implicated ( 46 , 47 ) based on known function of this molecule in regulating peripheral tolerance ( 48 ) and with neuritin produced by Tfr cells suppressing the development of autoantibodies and IgE class switching ( 45 ).…”

mentioning

confidence: 99%

“…Different allergy models with distinct response kinetics and different Tfr-deficient animals were used in these two settings, which may potentially explain the contrasting results. In addition, depleting Tfr cells but not Tregs specifically using SAP KO (which do not form Tfh or Tfr cells but do form Treg cells) and Foxp3-DTR (which lack Tfr cells) mixed bone marrow chimeras as well as Bcl6 flox/flox Foxp3-Cre animals following a similar protein immunization model resulted in decreased antigen-specific GC B cells ( 13 , 45 ).…”

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confidence: 99%

T Follicular Regulatory Cells: Choreographers of Productive Germinal Center Responses

Craft

2021

Front. Immunol.

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T follicular regulatory cells, or Tfr cells, are a discernable population of regulatory T (Treg) cells that migrate to the B cell follicle and germinal center (GC) upon immune challenge. These cells express the transcription factor Bcl6, the master regulator required for development and differentiation of T follicular helper cells, and are among a group of previously described Treg cells that use T helper cell–associated transcription factors to adapt their regulatory function to diverse milieus for maintenance of immune homeostasis. While there is consensus that Tfr cells control B-cell autoreactivity, it has been unclear whether they regulate productive, antigen-specific GC responses. Accordingly, understanding the regulatory balancing that Tfr cells play in maintenance of B-cell tolerance while optimizing productive humoral immunity is crucial for vaccine-design strategies. To this end, we discuss recent evidence that Tfr cells promote humoral immunity and memory following viral infections, fitting with the accepted role of Treg cells in maintaining homeostasis with promotion of productive immunity, while mitigating that which is potentially pathological. We also propose models in which Tfr cells regulate antigen-specific B cell responses.

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Increase in the prevalence of follicular regulatory T cells correlates with clinical efficacy of sublingual immunotherapy with house dust mites

Murao

Kouzaki

Arai

et al. 2023

Int Forum Allergy Rhinol

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BackgroundAllergic rhinitis (AR) impairs quality of life and affects nearly 40% of the Japanese population. Sublingual immunotherapy (SLIT) is the disease‐modifying treatment for AR, but requires the selection of a biomarker associate with clinical efficacy in patients with AR who are treated with SLIT. The present study sought to examine objective biomarkers used for assessing the clinical efficacy of SLIT.MethodsThe authors examined the effects of 1 year of SLIT treatment with house dust mites (HDMs) using peripheral blood mononuclear cells (PBMCs) and serum from patients with AR. The prevalences of follicular regulatory T (Tfr), type 2 follicular helper T (Tfh2), type 2 helper T (Th2), conventional regulatory T (Treg), and type 1 regulatory T (Tr1) cells were examined by flow cytometry. Serum concentrations of HDM‐specific IgA, IgE, and IgG4 antibodies, and HDM‐induced production of interleukin (IL) 5 and IL‐10 from cultured PBMCs were evaluated by enzyme‐linked immunosorbent assay.ResultsFollowing 1 year of SLIT, the prevalences of Tfr, conventional Treg, and Tr1 cells were significantly increased, whereas that of Th2 cells and Tfh2 cells were significantly decreased; the serum concentration of HDM‐specific IgG4 was significantly increased; and HDM‐induced production of IL‐5 from PBMCs was significantly decreased, while that of IL‐10 was significantly increased. The increase in the prevalence of Tfr cells after SLIT correlated positively with the improvement of clinical symptom scores.ConclusionAn increase in Tfr cells may play an important role in SLIT, and may be a useful indicator for the clinical efficacy of SLIT.

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Follicular regulatory T cells produce neuritin to regulate B cells

Cited by 117 publications

References 65 publications

PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

T Follicular Regulatory Cells: Choreographers of Productive Germinal Center Responses

Increase in the prevalence of follicular regulatory T cells correlates with clinical efficacy of sublingual immunotherapy with house dust mites

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