Interferon-γ Excess Leads to Pathogenic Accumulation of Follicular Helper T Cells and Germinal Centers

Lee, Sau K.; Silva, Diego G.; Martin, Jeffrey T.; Pratama, Alvin; Hu, Xin; Chang, Pheh-Ping; Walters, Giles; Vinuesa, Carola G.

doi:10.1016/j.immuni.2012.10.010

Cited by 219 publications

(226 citation statements)

References 61 publications

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“…TLR9/MyD88 signaling in DCs increased the magnitude of anti-NP IgG produced by promoting the expansion of T FH cells and GC B cells, whereas TLR9/MyD88 signaling in B cells primarily affected the quality of the GC response, resulting in better selection for high-affinity antibody, more class switching to IgG2a b , and a stronger secondary IgG response. Taken together, these data reveal that TLR9 signaling in multiple cell types cooperates to establish a coordinated GC reaction with characteristics previously demonstrated to be important in viral infection models, as well as in a mouse model of systemic lupus erythematosus (13,(41)(42)(43)(44).…”

Section: Discussionsupporting

confidence: 70%

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: Discussionsupporting

confidence: 70%

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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“…Moreover, both IFN-g and IL-17 are important for the generation and maintenance of GCs during autoimmune reactions (61). Our findings revealed that S. Typhi porins induce not only IFN-g, but also an IL-17A response in CD4 + T cells, and that both Ifngr 2 and Il17ra deficiency impacts on GC and antiporin Ab generation.…”

Section: Discussionmentioning

confidence: 59%

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

Pérez-Shibayama

Gil‐Cruz

Pastelin-Palacios

et al. 2014

The Journal of Immunology

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Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C– and F–based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4+ T cell–dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-γ–secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-γ and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM+ B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-γR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.

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“…However, it is possible that Tfh cells Our findings, in both TGF-βR-KO and TGF-βR-DN mice, indicated that T cells, either escaping or modulating TGF-β control, respectively, could accumulate spontaneously as Tfh cells. It is notable that these 2 mouse models have been associated with high levels of inflammatory cytokines such as IFN-γ (28, 49), which is known to lead to BCL6 overexpression and excessive development of Tfh cells (43). However, our work rules out any bystander cytokine action on Tfh cell population control in these mouse models, and thus underlines a direct effect of TGF-β on T cells to control Tfh cell homeostasis.…”

Section: Discussionmentioning

confidence: 74%

TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity

McCarron¹,

Marie²

2014

J. Clin. Invest.

101

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Interferon-γ Excess Leads to Pathogenic Accumulation of Follicular Helper T Cells and Germinal Centers

Cited by 219 publications

References 61 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

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity

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