Erratum: Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA

Yu, Daren; Tan, Andy Hee-Meng; Hu, Xin; Athanasopoulos, Vicki; Simpson, Nicholas; Silva, Diego G.; Hutloff, Andreas; Giles, Keith M.; Leedman, Peter J.; Lam, Kong-Peng; Goodnow, Christopher C.; Vinuesa, Carola G.

doi:10.1038/nature06729

Cited by 54 publications

(68 citation statements)

References 1 publication

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“…ICOS has been considered an inducible T-cell costimulatory molecule important for CD40-mediated Ab class switching [30]; however, the recent studies of uncontrolled expression of ICOS in several gene-modified mice showing lupus-like pathology provide insight for the close relationship between ICOS-expressing CD4 1 T cells and autoimmunity [19,31]. In the present study, blockade of ICOS using neutralizing Ab significantly reduced the production of total IgG in RASV-administered MyD88 À/À mice, suggesting possible cross-talk between Tfh-like cells and B cells via ICOS-ICOSL interaction for hyper-IgG.…”

Section: Discussionmentioning

confidence: 99%

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Yang

et al. 2011

Eur J Immunol

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The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88 À/À mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4 1 T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4 1 T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88 À/À mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1-and ICOSdependent manner.

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Section: Discussionmentioning

confidence: 99%

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Yang

et al. 2011

Eur J Immunol

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“…OX40, 4-1BB, and ICOS have been implicated in the pathogenesis of lupus. [42][43][44] OX40 and 4-1BB magnify the T-cell response through induction of the proliferation of conventional T cells and inhibition of T reg cell-mediated immune suppression. 37,45 The ICOS-mediated signal is essential for the induction of follicular helper T cells, thus it functions as an enhancer of B-cell response.…”

Section: Discussionmentioning

confidence: 99%

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

Abe

Ueha

Suzuki

et al. 2008

The American Journal of Pathology

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Foxp3 ؉ CD4 ؉ regulatory T (T reg ) cells play a pivotal role in the maintenance of dominant self tolerance. Understanding how the failures of immune control by T reg cells are involved in autoimmune diseases is important for the development of effective immunotherapies. In the present study, we analyzed the characteristics of endogenous T reg cells in (NZB ؋ NZW) F1 (BWF1) mice, a murine model of systemic lupus erythematosus. Unexpectedly, T reg number and frequency in aged BWF1 mice with developing lupus nephritis were increased, not decreased, and in vitro suppressive activity in lymphoid organs was intact. In addition, T reg cells trafficked to target organs because cells were present in the kidney and lung. T reg cells of aged BWF1 mice exhibited altered localization within lymph organs, however, and an altered phenotype, with higher expression levels of chemokine receptors and activation markers, suggesting a highly activated cellular state. Notably, the expression levels of costimulatory molecules were also markedly enhanced in the T reg cells of aged BWF1 mice. Furthermore, T reg cells of BWF1 mice did not show any suppressive effects on antibody production in vitro. Taken together, we conclude that T reg cells in BWF1 mice are not predisposed to functional incompetence but rather are present in a highly activated state. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology characterized by a massive production of autoantibodies against various nuclear antigens. The deposit of immune complexes in the target organs, ie, skin, kidney, lung, joints, and central nervous system, is thought to cause fatal dysfunction of the body system. (NZB ϫ NZW) F1 (BWF1) is a mouse strain that has been widely used as a model for SLE since the 1960s. These mice spontaneously develop severe autoimmune disease highly resembling human SLE in terms of serological and hematological abnormalities, and severe nephritis accompanying massive production of antinuclear antibodies. 1 Reconstitution of SCID (severe combined immunodeficiency) mice with cultured pre-B cells of BWF1 mice recapitulates many symptoms of the disease of BWF1 mice. Cultured pre-B cells alone, however, are not sufficient to fully reproduce the disease. 2 These data suggest that cellular subset(s) in addition to B cells are necessary for the development of the lupus-like syndrome of BWF1 mice, although abnormalities of the immune system predominantly lie within B cells. One of the possible candidates is CD4 ϩ T cells, because depletion of CD4 ϩ T cells with anti-CD4 antibody from 5 months old, slightly before the disease onset, prevents the development of the disease. 3,4 CD4 ϩ T cells are, therefore, also required for the development of the disease in BWF1 mice, possibly by providing help for the production of high-affinity autoantibodies.Studies in this decade have clearly shown the key roles of naturally occurring regulatory T (T reg ) cells in the maintenance of dominant self tolerance of the immune system. 5 T reg cells in normal mi...

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“…However, some studies showed that roquin represses autoimmunity by limiting ICOS mRNA expression through a microRNA-independent posttranslational repression. 33,34 In addition, a recent study showed that the loss of roquin induced early death and immune dysregulation but not autoimmunity in sanroque mice. 35 Therefore, future studies are required to completely elucidate the mechanisms behind pathogenesis of lupus in sanroque mice.…”

Section: T Fh Cells In Murine Models Of Autoimmune Diseasesmentioning

confidence: 99%

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

Shekhar

Yang

2012

Cell Mol Immunol

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Follicular helper T (T FH ) cells represent a distinct subset of CD4 1 helper T (T H ) cells specialized in providing help to B cells. They are characterized by their unique transcriptional profile (Bcl6), surface marker expression (CXCR5, PD-1, ICOS and CD40L) and cytokine production pattern (IL-21 and IL-6). T FH cells provide help to B cells both to form germinal centers (GCs) and to differentiate into memory B cells and plasma cells for generation of humoral responses. However, there is emerging evidence that implicates T FH cells in the development of various human pathologies, such as autoimmune diseases, immunodeficiency and lymphoma. This review focuses on the current progress in this area including mouse and human studies. A clearer understanding of the mechanisms of T FH cell-mediated immunity and pathology may be exploited for rational development of therapeutic strategies.

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Erratum: Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA

Cited by 54 publications

References 1 publication

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

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