T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance

Rubtsova, Kira; Rubtsov, Anatoly V.; Dyk, Linda F. van; Kappler, John W.; Marrack, Philippa

doi:10.1073/pnas.1312348110

Cited by 244 publications

(349 citation statements)

References 55 publications

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“…Interestingly, inclusion of a TLR9 ligand in the antigen resulted in substantially decreased IL-4 mRNA and increased IFN-γ mRNA (Fig. S3B), which is consistent with the observed increase in isotype switching to IgG2a b (32,33). Thus, differential modulation of cytokine and costimulatory pathways of T FH cells likely established distinct selection pressures in the GC reactions occurring in the presence or absence of a TLR9 ligand.…”

Section: Tlr9supporting

confidence: 75%

“…In contrast, the class switch to IgG2a was similar in both Myd88 −/− and Myd88 +/+ B cells in mixed bone marrow chimeras, whereas it was defective if all B cells were Myd88 −/− . Therefore, we hypothesize that Myd88 +/+ B cells in the GC of mixed bone marrow chimeric mice were able to promote the ability of T FH cells to induce B cells of either genotype to class switch to IgG2a, for example, by production of IFN-γ (32,33,68). Alternatively, prior studies have demonstrated that in some immunizations, the class switch to IgG2a can be a B cell-intrinsic function of TLR9 signaling (6,69).…”

Section: Discussionmentioning

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: Tlr9supporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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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“…These data indicate that aged female mice accumulate ABCs (49, 121-123), a subset of B cells defined by the expression of cell surface CD11c and the transcription factor T-bet (49,123,124). We have also reported that ABCs accumulate in several different mouse models of SLE (MRL lpr , NZB/NZW, MER -/-) and coincide with the appearance of autoantibodies (49, 50).…”

Section: Sex-dependent Changes In the Aging Immune Systemmentioning

confidence: 86%

“…We have identified TLR7, IFNGR, and B cell antigen receptor signaling as necessary and sufficient for the upregulation of T-bet expression in B cells (123,124), which eventually causes B cells to assume the ABC phenotype. We have confirmed that TLR7 is most efficient in driving this process when compared with other TLRs (124).…”

Section: Acknowledgmentsmentioning

confidence: 99%

Sexual dimorphism in autoimmunity

Rubtsova¹,

Marrack²,

Rubtsov³

2015

J. Clin. Invest.

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170

127

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R e v i e w S e R i e S : A u t o i m m u n i t y 2 1 8 8jci.org Volume 125 Number 6 June 2015expression of IFN1 genes is controlled directly by sex hormones. On the other hand, sex hormones do affect expression of some of the PRRs (see below) and in this way might indirectly affect IFN1 levels. Thus, the abundance of IFN1s in lupus patients might be caused by female sex hormone-induced increases in PRR levels, which in turn increase production of IFN1s. One of the genes that controls expression of IFN1s is IFN regulatory factor 5 (IRF5). IRF5 has also been identified as a significant risk factor for lupus susceptibility (37,38). Expression of IRF5 in mice has been reported to be sex dependent (39). As demonstrated by Shen and colleagues (39), C57BL/6, NZB, Nba2, NZB/NZW F1, and NZM mouse strains express significantly higher levels of Irf5 mRNA in female than in male lymphocytes. Additionally, splenocytes from lupus-prone mice were shown to express higher levels of Irf5 mRNA compared with cells from the C57BL/6 strain, which is not prone to lupus. This group further demonstrated that Irf5 expression can be upregulated in vitro upon estrogen treatment, suggesting a potential mechanism for sex-biased expression of the gene and consequent overproduction of IFN1s (39).Absence of IFN-γ signaling protects NZB/NZW F1 mice against lupus-like disease (40). Expression of the IFNG gene, on the other hand, is regulated directly by estrogens (41)(42)(43)(44)(45). This finding suggests a positive feedback loop between the IFNs and estrogens, since activation of IFN1 or IFN-γ signaling upregulates the expression of ERα (46). Estrogen, in turn, promotes IFN-γ production by various lymphocytes. In addition, Panchanathan et al. demonstrated synergistic involvement of ERα and IFN signaling in activating the transcription of both IFN and estrogen-responsive target genes (46).Once produced, IFNs have many effects on the immune system that contribute to the sex bias of autoimmunity. For example, IFN1s increase class 1 MHC expression on cells, and IFN-γ induces class II MHC and changes the nature of the proteasome, thereby affecting the nature and quantity of self-peptides presented to T cells. Other examples are described below. Other immune-associated genes affected by sex hormonesMany genes with products that affect the immune system are controlled by sex hormones. As far as innate immunity is concerned, estrogens induce the expression of intracellular but not surface TLRs in both male and female PBMCs (23). Because intracellular TLRs have been shown to affect the development of autoimmunity (47-51), it is possible that the hormonal effect of the expression of intracellular TLRs contributes to female-biased autoimmunity.Unc-93 homolog B1 (UNC93B1) is an endoplasmic reticulum (ER) transmembrane protein that is essential for trafficking the TLRs that are expressed intracellularly (TLR3, TLR7, TLR8, TLR9, and probably other TLRs) from the ER to endosomes (52-54). UNC93B1 regulates the activity of these TLRs by mediating localization t...

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“…9 Other immune cells such as natural killer, dendritic, B, and CD8-positive-T cells also express T bet. [10][11][12][13][14] The T-bet has a pleiotropic role, directs the expression of interleukin 1α, macrophage inflammatory protein-1α in dendritic cells, 15 interferon γ in Th1 cells, 16 and class switching in B cells. 17 A recent study revealed that intraglomerular T-bet expression is associated with antibody-mediated rejection in Chinese people.…”

Section: T-bet-positive Mononuclear Cell Infiltration Is Associated Wmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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T-box transcription factor T-bet, a key player in a unique type of B-cell activation essential for effective viral clearance

Cited by 244 publications

References 55 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

Sexual dimorphism in autoimmunity

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