TCR recognition of peptide/MHC class II complexes and superantigens

Sundberg, Eric J.; Deng, Lu; Mariuzza, Roy A.

doi:10.1016/j.smim.2007.04.006

Cited by 99 publications

(81 citation statements)

References 67 publications

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“…1 SAgs bind directly to lateral surfaces of MHC class II molecules, and to select TCR b-chain variable domains (Vb), and these unconventional contacts can lead to the activation and expansion of a large fraction of exposed T cells in a Vbrestricted manner. 2 Through this mechanism, SAgs may ultimately cause a cytokine storm that is responsible for many hallmark features of SAg-induced morbidity, including the most severe form of SAg-mediated disease known as toxic shock syndrome.…”

mentioning

confidence: 99%

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

et al. 2011

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Invariant NKT (iNKT) cells are infrequent but important immunomodulatory lymphocytes that exhibit CD1d-restricted reactivity with glycolipid Ags. iNKT cells express a unique T-cell receptor (TCR) composed of an invariant a-chain, paired with a limited range of b-chains. Superantigens (SAgs) are microbial toxins defined by their ability to activate conventional T cells in a TCR b-chain variable domain (Vb)-specific manner. However, whether iNKT cells are directly activated by bacterial SAgs remains an open question. Herein, we explored the responsiveness of mouse and human iNKT cells to a panel of staphylococcal and streptococcal SAgs and examined the contribution of major histocompatibility complex (MHC) class II and CD1d to these responses. Bacterial SAgs that target mouse Vb8, such as staphylococcal enterotoxin B (SEB), were able to activate mouse hybridoma and primary hepatic iNKT cells in the presence of mouse APCs expressing human leukocyte antigen (HLA)-DR4. iNKT cell-mediated cytokine secretion in SEB-challenged HLA-DR4-transgenic mice was CD1d-independent and accompanied by a high interferon-c:interleukin-4 ratio consistent with an in vivo Th1 bias. Furthermore, iNKT cells from SEB-injected HLA-DR4-transgenic mice, and iNKT cells from SEB-treated human PBMCs, showed early activation by intracellular cytokine staining and CD69 expression. Unlike iNKT cell stimulation by a-galactosylceramide, stimulation by SEB did not induce TCR downregulation of either mouse or human iNKT cells. We conclude that Vb8-targeting bacterial SAgs can activate iNKT cells by utilizing a novel pathway that requires MHC class II interactions, but not CD1d. Therefore, iNKT cells fulfill important effector functions in response to bacterial SAgs and may provide attractive targets in the management of SAg-induced illnesses.

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confidence: 99%

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

et al. 2011

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“…Genetic variants in antigen presenting HLA genes have been associated with over 100 diseases, including the vast majority of autoimmune disorders (29). While the specific mechanisms behind the associations with autoimmune disease remain unclear, it is thought that the particular disease associated variants might enhance the binding or presentation of specific self-peptides to the T-cell receptor, increasing the potential for development of an autoimmune response (30). Due to the long held realization of HLA involvement with autoimmunity, it is not surprising that the majority of past efforts at deciphering the genetics of PBC have focused on this region.…”

Section: Mhc -Hlamentioning

confidence: 99%

Genetics and Genomics of Primary Biliary Cirrhosis

Juran

Lazaridis

2008

Clinics in Liver Disease

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The etiological and pathogenic factors contributing to PBC development, progression, response to treatment, and ultimately, outcome remain a mystery. This lack of knowledge can be attributed to the complexity of PBC, wherein a number of environmental triggers may be culpable, but require coexisting genetic susceptibility to exert their effect. Recognition of the genomic regions harboring these heritable risk factors has been hindered by the rarity and late onset of PBC, which has rendered the collection of adequate numbers of patients and family members for genetic analyses a difficult task. Recent advancements in the discipline of genomics holds promise to fundamentally change our understanding, prevention, and therapy of PBC. This chance arises from the development of new high-throughput approaches to genotyping, providing the means to rapidly uncover many of the genetic polymorphisms that are relevant to disease. In order to move ahead, large registries and biospecimen repositories of patients with PBC, their family members, and well-matched controls need to be established, maintained, and continually expanded. At the same time, sizeable, comprehensive haplotype mapping based association studies of functionally plausible candidate gene groups (e.g. immune function genes) as well as more far reaching genome-wide association studies will be necessary to form the basis upon which the genetic predisposition to PBC can be defined. This first set of experimental data will provide the means for future fine mapping studies, resequencing efforts, functional experimentation, and elucidation of gene-environment and gene-gene interaction; perhaps paving new paths in PBC research.

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“…Staphylococcal enterotoxins are extremely potent activators of T-cells and they bind directly to the major histocompatibility complex (MHC) class II molecules on antigen presenting cells (APCs) and to variable β chains on T-cell antigen receptors [14] [15] [16]. Under normal conditions, specific proliferation, co-stimulatory recognition and verification signals are required for T-cell activation.…”

Section: Introductionmentioning

confidence: 99%

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

Whitfield¹,

Risdall²,

Griffiths³

et al. 2017

ABB

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Staphylococcal Enterotoxin B (SEB) is considered a potential biological weapon. It is toxic by both inhalation and ingestion. Effects of ingestion include fever, vomiting and diarrhoea, while inhalation may additionally result in chest pain, dyspnoea, pulmonary oedema and respiratory failure. Severe exposure may be fatal and treatment relies on symptomatic support. At a cellular level, SEB up-regulates T-cell proliferation leading to a pathological inflammatory response. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae), has been shown to reduce cellular proliferation by inhibiting the phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway. Using isolated murine splenocytes, we have demonstrated that treatment with deguelin reduces SEB inducing T cell proliferation by 60%. Deguelin treatment also decreased IL-2 and CCL2 secretion by splenocytes exposed to SEB. We demonstrate that targeting cellular proliferation can significantly reduce inflammation after SEB exposure and suggest that antiproliferatives may have a role as potential generic medical counter measures if superantigens are used as biological weapons.

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TCR recognition of peptide/MHC class II complexes and superantigens

Cited by 99 publications

References 67 publications

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

Genetics and Genomics of Primary Biliary Cirrhosis

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

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