A Costimulatory Function for T Cell CD40

Munroe, Melissa E.; Bishop, Gail A.

doi:10.4049/jimmunol.178.2.671

Cited by 100 publications

(100 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1D), correlating CD40 expression with self-antigen presentation. Although functional CD40 expression has been reported on thymocytes and peripheral T cells (24,25), we found no expression of CD40 on activated CD4 ϩ T cells or CD4SP thymocytes (SI Fig. 5 C and D).…”

Section: Cd40-expressing Thymic Dendritic or Epithelial Cells Can Procontrasting

confidence: 44%

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Spence

Green

2008

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

View full text Add to dashboard Cite

Foxp3 ؉ regulatory T cells develop in the thymus and are essential for maintaining peripheral tolerance to self tissues. We report the critical requirement for CD154 up-regulation specifically on, and during the thymic development of, Foxp3 ؉ regulatory T cells for the induction of their clonal expansion within the medulla. In the absence of this signal, there was a severe reduction in their thymic generation and output, leading to decreased peripheral numbers. Importantly, CD40 expression on either thymic dendritic or epithelial cells was sufficient to promote the development of normal numbers of Foxp3 ؉ regulatory T cells. This work suggests that CD154-transduced signals promote Foxp3 ؉ regulatory T cell development and highlights the plasticity of the thymic stroma for supporting their generation. Crucially, this study demonstrates that Foxp3 ؉ regulatory T cells can promiscuously accept a single critical signal necessary for their thymic development from different cellular sources, redefining our understanding of their generation.CD154 ͉ thymus ͉ thymic epithelial cells ͉ CD40 R egulatory T cells (Tregs) actively suppress autoreactive T cells, thereby limiting aberrant immune responses and maintaining tolerance toward self tissues (1). Deficiencies in this T cell subset in humans and mice can lead to severe autoimmunity. Initially, these suppressor cells were identified as CD4 ϩ CD25 ϩ T cells (2), a phenotype that also included activated CD4 ϩ T cells, but, recently, Foxp3 has been characterized as the master regulator of their development and function (3-5) and is used as a highly specific marker for Tregs (6). Foxp3 ϩ Tregs develop in the thymus as part of the normal T cell ontogeny processes (7), and Foxp3 expression is largely restricted to the thymic medulla and CD4 ϩ CD8 Ϫ (CD4SP) thymocyte subset; the end stage of CD4 ϩ T cell development. Thymic output of Foxp3 ϩ Tregs is temporally delayed (8), and their development requires a highaffinity self-reactive T cell receptor (9, 10), the costimulatory molecule CD28 (11), and possibly IL-2 (12). It has been suggested that medullary thymic epithelial cells (mTECs), which express and present tissue-specific antigens (TSAs) on MHC class II (MHC II) molecules, drive Foxp3 ϩ Treg selection (13). Similarly, dendritic cells (DCs) are thought to induce CD4 ϩ CD25 ϩ Tregs in the human thymus through a T cell antigen receptor (TCR)-peptide-MHC II interaction (14). However, the relative contributions of thymic dendritic and epithelial cells in promoting and supporting the development of a polyclonal Foxp3 ϩ Treg repertoire are not clear. In addition, the cellular origin and temporal importance of the signals necessary for Foxp3 ϩ Treg development have not been determined, and, therefore, the rules governing how developing Foxp3 ϩ Tregs receive and process these signals are poorly understood.We report that the CD40-CD154 pathway is critical for promoting the thymic development of Foxp3 ϩ Tregs. CD154 up-regulation specifically on developing Foxp3 ϩ Tregs promoted the...

show abstract

Section: Cd40-expressing Thymic Dendritic or Epithelial Cells Can Procontrasting

confidence: 44%

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Spence

Green

2008

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

View full text Add to dashboard Cite

show abstract

“…In the classic concept of costimulation, CD40 ligation is required to efficiently activate B cells. However, CD40 has also been shown to provide costimulation to T cells, 31 promoting T-cell proliferation and attenuating proinflammatory cytokine release. 32,33 In line with this concept, activation of CD40 on T cells has been shown to be part of a novel coinhibitory suppression loop by which CD40L-expressing cells such as B cells inhibited overactivation of T cells by abrogating proinflammatory cytokines and promoting protective signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

et al. 2014

View full text Add to dashboard Cite

T he metabolic syndrome comprises a cluster of risk factors, including obesity, insulin resistance, hepatic steatosis, and dyslipidemia. It is associated with a variety of cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke.1 Chronic, low-grade inflammation in key metabolic organs such as the liver and visceral adipose tissue (VAT) Background-Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. Methods and Results-To induce the metabolic syndrome, wild-type or CD40 −/− mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40−/− mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1 −/− mice with CD40 −/− T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. Conclusions-We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease. T-regulatory (T reg ) cells, CD8 + T cells, and related chemokines and cytokines such as RANTES (regulated on activation normal T cell expressed and secreted) and interferon-γ (IFNγ) colocalize within the inflammatory cell compartment in adipose tissue. 7 In lean adipose tissue, the vast majority of T lymphocytes share features of anti-inflammatory, interleukin (IL)-13-, IL-4-, and IL-10-secreting Th2 or T reg cells. 8In obesity, proinflammatory Th1 cells expressing IFNγ overwhelm Th2 cells.9 Th1 cells, in turn, activate proinflammatory cytokine-secreting macrophages and promote their conversion from M2-like, IL-10-secreting, alternatively activated macrophages to classically activated, M1-like macrophages. 10,11Despite description of the kinetics of cellular infiltration and the associated cytokine/chemokine profiles during the development of obesity, the underlying cause modu...

show abstract

“…Aberrant signaling through the CD40 pathways has been implicated in the pathogenesis of several autoimmune diseases, including GD (17)(18)(19). Fibrocytes from patients with TAO have higher levels of CD40 than do those from healthy donors (20).…”

Section: Introductionmentioning

confidence: 99%

Thyrotropin and CD40L Stimulate Interleukin-12 Expression in Fibrocytes: Implications for Pathogenesis of Thyroid-Associated Ophthalmopathy

Mester

Gupta

et al. 2016

Thyroid

View full text Add to dashboard Cite

A Costimulatory Function for T Cell CD40

Cited by 100 publications

References 97 publications

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

Thyrotropin and CD40L Stimulate Interleukin-12 Expression in Fibrocytes: Implications for Pathogenesis of Thyroid-Associated Ophthalmopathy

Contact Info

Product

Resources

About

A Costimulatory Function for T Cell CD40

Cited by 100 publications

References 97 publications

Foxp3+regulatory T cells promiscuously accept thymic signals critical for their development

Foxp3+regulatory T cells promiscuously accept thymic signals critical for their development

Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

Thyrotropin and CD40L Stimulate Interleukin-12 Expression in Fibrocytes: Implications for Pathogenesis of Thyroid-Associated Ophthalmopathy

Contact Info

Product

Resources

About

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development

Foxp3⁺regulatory T cells promiscuously accept thymic signals critical for their development