T regulatory cells participate in the control of germinal centre reactions

Alexander, Carla Maria; Tygrett, Lorraine T.; Boyden, Alexander W.; Wolniak, Kristy L.; Legge, Kevin L.; Waldschmidt, Thomas J.

doi:10.1111/j.1365-2567.2011.03456.x

Cited by 62 publications

(94 citation statements)

References 83 publications

(346 reference statements)

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“…Although T FH cells can be thought of as positive regulators of GCs, most data suggest a restrictive role for T FR cells (17)(18)(19)(20)(21)(22)59). We found that TLR9/MyD88 signaling in both DCs and B cells affected the relative balance between T FH and T FR cells in the GC.…”

Section: Discussionmentioning

confidence: 69%

“…Although the function of T FR cells is not fully understood, it may include negative regulation of both T FH cells and B cells during a GC response (17)(18)(19)(20)22). T FR cells were identified as CD4 + CD44 + CD62L − PD-1 + CXCR5 + FoxP3 + (Fig.…”

Section: Tlr9-stimulated Dcs and B Cells Differentially Regulate T Fhmentioning

confidence: 99%

mentioning

confidence: 99%

“…This receptor allows T FH cells to access GCs, where they provide survival and selection cues to antigen-presenting B cells through T-cell receptor (TCR) recognition of antigenic peptide-MHC II complexes, costimulatory ligandreceptor pairs, and cytokine production (8,15,16). Recently, it has become clear that some follicular CXCR5 + CD4 + T cells are thymically derived FoxP3 + regulatory T cells, referred to as follicular regulatory T (T FR ) cells (17)(18)(19)(20)(21)(22). Although their function is poorly understood at this point, T FR cells appear to limit the size of the GC response (17)(18)(19)(20).…”

mentioning

confidence: 99%

“…Recently, it has become clear that some follicular CXCR5 + CD4 + T cells are thymically derived FoxP3 + regulatory T cells, referred to as follicular regulatory T (T FR ) cells (17)(18)(19)(20)(21)(22). Although their function is poorly understood at this point, T FR cells appear to limit the size of the GC response (17)(18)(19)(20).Several studies have shown that physical linkage of a TLR7 or TLR9 ligand to a particulate antigen can substantially boost the GC response and lead to greater production of high-affinity antibody (5, 11, 12); however, the mechanisms underlying these effects are poorly understood. Moreover, previous studies were limited in their ability to compare a pathogen infection, a virus-like particle, or nanoparticle immunization with an immune response lacking PAMPs.…”

mentioning

confidence: 99%

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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: 69%

Section: Tlr9-stimulated Dcs and B Cells Differentially Regulate T Fhmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

2012

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The potential for self‐reactive T cells to cause autoimmune disease is held in check by Foxp3+ regulatory T cells (Tregs), essential mediators of peripheral immunological tolerance. Tregs have the capacity to suppress multiple branches of the immune system, tightly controlling the different subsets of effector T cells across multiple different tissue environments. Recent genetic experiments have found mutations that disrupt specific Treg: effector T cell relationships, leading to the possibility that subsets of Tregs are required to suppress each subset of effector T cells. Here we review the environmental factors and mechanisms that allow Tregs to suppress specific subsets of effector T cells, and find that a parsimonious explanation of the genetic data can be made without invoking Treg subsets. Instead, Tregs show a functional and chemotactic plasticity based on microenvironmental influences that allows the common pool of cells to suppress multiple distinct immune responses.

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Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

Grötsch¹,

Lux

Rombouts

et al. 2019

Journal of Bone and Mineral Research

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Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG‐rheumatoid factor (IgG‐RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG‐RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG‐RF production by plasma cells and regulates autoimmune‐mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell) led to increased IgG1‐producing bone marrow plasma cells, enhanced IgG‐RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG‐RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T‐cell‐dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast‐mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG‐RF production and autoimmune‐mediated bone loss. © 2019 American Society for Bone and Mineral Research.

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T regulatory cells participate in the control of germinal centre reactions

Cited by 62 publications

References 83 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

Immune tolerance: Are regulatory T cell subsets needed to explain suppression of autoimmunity?

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

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