Cutting Edge: CTLA-4–B7 Interaction Suppresses Th17 Cell Differentiation

Ying, Haiyan; Yang, Lifen; Qiao, Guilin; Li, Zhenping; Zhang, Li; Yin, Fei; Xie, Dong; Zhang, Jian

doi:10.4049/jimmunol.0903369

Cited by 90 publications

(76 citation statements)

References 20 publications

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“…The length of the CDR3 region has previously been implicated in the differentiation of Tconv cells to either a Th1 or Th2 phenotype (53). Similarly, CTLA-4-deficient mice have been shown to exhibit a skewed repertoire of Th1, Th2, and Th17 cells, which was also reported here for Tg4 CTLA-4KO mice (28,(35)(36)(37)). In our model, CDR3α using the endogenous TRAV13 showed a greater diversity in length in Treg cells than Tconv cells, which was previously found by one group (43), although other groups have found a comparable (44) or lower (45) diversity in different models.…”

Section: Discussionsupporting

confidence: 77%

“…This effect was unexpected, because CTLA-4 is not expressed on splenic Tconv cells until at least 24 h after activation (34). Accordingly, alterations in IL-4 and IL-17 production in other CTLA-4KO models did not occur until after a second TCR stimulation (28,(35)(36)(37). The observed effect on IL-10 production has not been reported previously to our knowledge.…”

Section: Ctla-4 Is Expressed Mainly By Thymocytes In the Corticomedulmentioning

confidence: 65%

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CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen

Genolet

Britton

et al. 2012

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

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Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3 + regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3 + Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4 + CD8 − thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.costimulation | immune regulation | experimental autoimmune encephalomyelitis

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Section: Discussionsupporting

confidence: 77%

Section: Ctla-4 Is Expressed Mainly By Thymocytes In the Corticomedulmentioning

confidence: 65%

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen

Genolet

Britton

et al. 2012

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

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“…Malt1 -/-mice were originally generated in our laboratory (20,37) and backcrossed for more than 10 generations into the C57BL/6 backIn vitro, IL-6, IL-21, and IL-23 -with or without TGF-β -have been reported to induce Th17 cell differentiation or stabilization (5,11,12,44,45). However, the roles of TCR stimulation and costimulatory signaling in the differentiation of specific Th subsets have yet to be clearly delineated (46)(47)(48)(49). Engagement of both the TCR and CD28 results in activation of the IKK complex, which relieves NF-κB from its suppression by the IκB proteins.…”

Section: Methodsmentioning

confidence: 99%

The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

Brüstle¹,

Brenner²,

Knobbe³

et al. 2012

J. Clin. Invest.

108

123

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“…However, CTLA-4 signalling suppresses Th17 generation and, as discussed above, IL-17 may have a direct role in stimulating B cell autoantibody production, suggesting that treatment of RA with CTLA-4-Ig may lead to reduced ACPA levels [96].…”

Section: Blockade Of T Cell Co-stimulation With Ctla-4-ig (Abatacept)mentioning

confidence: 96%

The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses

Modi

Soejima

Levesque

2013

Clinical and Experimental Immunology

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SummaryRheumatoid arthritis (RA) is a complex inflammatory disorder associated with synovitis and joint destruction that affects an estimated 1·3 million Americans and causes significant morbidity, a reduced life-span and lost work productivity. The use of biological therapies for the treatment of RA is costly, and the selection of therapies is still largely empirical and not guided by the underlying biological features of the disease in individual patients. The synovitis associated with RA is characterized by an influx of B and T cells, macrophages and neutrophils and the expansion of fibroblast-like synoviocytes, which form pannus and lead to cartilage and bone destruction. RA is associated with synovial production of rheumatoid factor (RF) and anticitrullinated protein autoantibodies (ACPA) and with the production of inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-17 and tumour necrosis factor (TNF)-a, which are targets for RA therapeutics. Recent ideas about the pathogenesis of RA emphasize a genetic predisposition to develop RA, a preclinical phase of disease that is associated with the production of ACPA and the development of symptomatic disease following inflammatory initiating events that are associated with expression of citrullinated epitopes in the joints of patients. However, we still have a limited understanding of the cytokine and intracellular pathways that regulate ACPA levels. In humans, therapy with biological agents affords a unique opportunity to better understand the cytokine and signalling pathways regulating ACPA levels and the impact of ACPA level changes on disease activity. In this study we summarize the effect of RA therapies on ACPA levels and B cell responses.

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Cutting Edge: CTLA-4–B7 Interaction Suppresses Th17 Cell Differentiation

Abstract: Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/07/06/jimmunol.090336

Cited by 90 publications

References 20 publications

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

The NF-κB regulator MALT1 determines the encephalitogenic potential of Th17 cells

The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses

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