The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut

Kawamoto, Shimpei; Tran, Thinh Huy; Maruya, Mikako; Suzuki, Keiichiro; Doi, Yasuko; Tsutsui, Yumi; Kato, Lucia; Fagarasan, Sidonia

doi:10.1126/science.1217718

Cited by 401 publications

(356 citation statements)

References 33 publications

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“…PD-1 is an inhibitory receptor in the context of effector T-cell responses (51), and its blockade is associated with T FH cell expansion (52,53), consistent with an inhibitory role for PD-1 on T FH cells as well. ICOSL/ICOS costimulatory signals at the time of DC priming are critical for T FH cell development (25-27, 38, 54).…”

Section: Discussionmentioning

confidence: 97%

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Rookhuizen

DeFranco

2014

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated important roles of nucleic acidsensing Toll-like receptors (TLRs) in promoting protective antibody responses against several viruses. To dissect how recognition of nucleic acids by TLRs enhances germinal center (GC) responses, mice selectively deleted for myeloid differentiation primaryresponse protein 88 (MyD88) in B cells or dendritic cells (DCs) were immunized with a haptenated protein antigen bound to a TLR9 ligand. TLR9 signaling in DCs led to greater numbers of follicular helper T (T FH ) cells and GC B cells, and accelerated production of broad-affinity antihapten IgG. In addition to modulating GC selection by increasing inducible costimulator (ICOS) expression on T FH cells and reducing the number of follicular regulatory T cells, MyD88-dependent signaling in B cells enhanced GC output by augmenting a class switch to IgG2a, affinity maturation, and the memory antibody response. Thus, attachment of a TLR9 ligand to an oligovalent antigen acted on DCs and B cells to coordinate changes in the T-cell compartment and also promoted B cell-intrinsic effects that ultimately programmed a more potent GC response.T he ability of the innate immune system to survey infection relies on pattern recognition receptors, such as Toll-like receptors (TLRs), that signal through myeloid differentiation primary-response protein 88 (MyD88) upon recognition of pathogen-associated molecular patterns (PAMPs). Recognition of infection by TLRs shapes adaptive immunity by directing dendritic cells (DCs) to activate naive T cells (1-3), by directing T helper (T H ) 1 and T H 17 polarization of effector T cells (3, 4), and by promoting B-cell activation and terminal differentiation to antibody-secreting plasma cells (5, 6).Following infection or vaccination, antibody responses generally proceed in two phases: an initial extrafollicular response, which rapidly generates short-lived plasmablasts that secrete low-affinity IgM and small quantities of isotype-switched antibodies (7), and a slower germinal center (GC) response, where B cells switch Ig isotype, increase affinity for antigen through somatic mutation of IgH and IgL genes, and undergo selection processes (8). Importantly, the GC builds protection from reinfection by selecting long-lived plasma cells and memory B cells from cells expressing isotype-switched, affinity-matured Bcell antigen receptors (BCRs) (9). Initially, it was proposed that TLR signaling selectively favored the extrafollicular component of serological immunity (10), but it was shown subsequently that TLR signaling in B cells could greatly augment the GC response to virus-like particles, nanoparticles, and virions (5,11,12). Moreover, the ability of B-cell TLRs to enhance the antibody response was recently shown to be important for host defense of mice infected with Friend virus and the chronic version of lymphocytic choriomeningitis virus (LCMV) (12)(13)(14).Follicular helper T (T FH ) cells maintain the GC and govern selection for GC B cells with increased affinity for antigen (...

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Section: Discussionmentioning

confidence: 97%

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Rookhuizen

DeFranco

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Tfh cell regulation within the GC is mediated in part by inhibitory receptors, negative feedback loops, and the availability of antigen and growth factors, and it is also regulated by specialized populations of regulatory cells. The inhibitory receptor PD‐1 is expressed at high levels on Tfh cells, and engagement of PD‐1 by PD‐L1 on B cells prevents Tfh cell proliferation following antigen recognition on B cells 109, 220, 221. In addition to B cells, antigen‐specific plasma cells can also present antigen to Tfh cells.…”

Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 99%

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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“…The skewed gut microbial communities and the leaky gut barrier leads to a generalized activation of self-reactive B and T cells and production of autoantibodies. 59 Therefore, we surmise that any compound compromising the intestinal barrier integrity and/or the innate mucosal immunity and/or directly the gut microbiota will affect the functional equilibrium of this compartment and cause symptoms, as well as distant immunological perturbations.…”

Section: Microbiome and Therapeuticsmentioning

confidence: 99%

Gut microbiome and anticancer immune response: really hot Sh*t!

Viaud¹,

Daillère²,

Boneca³

et al. 2014

Cell Death Differ

113

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The Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut

Cited by 401 publications

References 33 publications

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

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

Gut microbiome and anticancer immune response: really hot Sh*t!

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