High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR

Fraser, John D.

doi:10.1038/339221a0

Cited by 378 publications

(239 citation statements)

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“…No inhibition of AICD in vitro was detected upon FLIP S overexpression. The absence of an AICD defect in vivo was confirmed by the observed normal deletion of reactive Vb8 + T cells after their initial expansion upon SEB injection into FLIP S -transgenic mice ( [38]; data not shown).…”

Section: Resultsmentioning

confidence: 77%

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

et al. 2005

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The cellular homologues of the viral anti-apoptotic v-FLIP proteins exist as a long (c-FLIP L ) and a short (c-FLIP S ) splice variant. While c-FLIP S and v-FLIP are composed solely of two death effector domains, c-FLIP L contains an (inactive) caspase-like domain in addition to these two death effector domains, thereby structurally resembling proCaspase-8. Both c-FLIP L and c-FLIP S suppress apoptosis by inhibiting Caspase-8 activation, although at different levels of pro-Caspase-8 processing. To analyze the consequences of deregulated c-FLIP S expression in vivo, we established lck FLIP Stransgenic mice overexpressing the transgene in thymocytes and in mature T cells. As expected, CD95L-induced apoptosis was impaired in lck FLIP S -transgenic T cells, indicating the functionality of the FLIP S transgene. Remarkably, activation-induced cell death of transgenic T cells was unaffected, despite the observed inhibition of CD95-induced T cell death. Thymic and splenic cell numbers as well as CD4/CD8 cellularity were normal in lck FLIP S -transgenic animals, which in contrast to CD95-deficient mice do not accumulate Thy1 + B220 + CD4 -CD8 -peripheral T cells. c-FLIP S overexpression leads to a significant decrease in activation-induced T cell proliferation in vitro. Despite the capacity of FLIP S to inhibit CD95-induced apoptosis, T cell lymphomagenesis is not observed in lck FLIP S -transgenic mice. Interestingly, the Vb8 + memory T cell pool is enlarged upon staphylococcal enterotoxin B injections, suggesting a specific in vivo function for FLIP S in the maintenance of restimulated T cells. IntroductionAmong many anti-apoptotic regulatory proteins, the Caspase-8-inhibitory FLIP molecule has been studied intensively. Originally detected in different viruses, c-FLIP was eventually identified as the cellular homologue of the v-FLIP proteins ([1, 2] and references herein). Several spliced isoforms of c-FLIP have been characterized, two of which are expressed as proteins: c-FLIP L , the full-length 55-kDa form of c-FLIP, comprises two Nterminal death effector domains (DED) and an enzymatically inactive caspase domain, thereby structurally resembling . c-FLIP S is a shorter 26-kDa form of c-FLIP and, like v-FLIP, contains only the two DED.A functional pro-apoptotic death-inducing signaling complex (DISC) is usually assembled by recruitment of the adaptor protein FADD to the activated CD95 receptor via death domain interactions [3]. Due to binding of their DED, FADD then associates Caspase-8 Molecular immunologyThe first two authors contributed equally to this work. [2,5]. Recruitment of both c-FLIP L and c-FLIP S to the activated intracellular CD95 receptor complex by FADD has been demonstrated, and both proteins are able to inhibit CD95-induced apoptosis as well as cell death mediated by other death receptors [6]. It has even been suggested that c-FLIP S rather than c-FLIP L may be the prime inhibitor of CD95-mediated apoptosis in T cells [7]. Nevertheless, a recent study showed that whereas high levels of c-FLIP L o...

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Section: Resultsmentioning

confidence: 77%

“…4C). T cells with a Vb6 T cell receptor b chain are not responsive towards SEB superantigen [38], and their constant percentage among peripheral T cells before and after SEB injection served as a control for this experiment. After 48 h, the expansion of Vb8-positive CD8 + T cells upon SEB stimulation was clearly detectable.…”

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confidence: 99%

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

et al. 2005

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“…binding of toxin to MHC class II molecules is a prerequisite for presentation by LG2 to the T cell hybridomas (6,(21)(22)(23), it is possible that B87 and 2B33 mAbs could have blocked the T cell hybridoma response either by blocking binding of SEB to MHC or by blocking T cell recognition of the toxin/MHC complex. To distinguish these possibilities we tested the ability of the mAbs either to interfere directly with SEB binding to MHC class II or to detect SEB already bound to MHC class II.…”

Section: Correlation Of Mab 2b33 and Drl-biruting Site On See Sincementioning

confidence: 99%

Monoclonal antibodies defining functional sites on the toxin superantigen staphylococcal enterotoxin B.

Hamad

Herman

Marrack

et al. 1994

The Journal of Experimental Medicine

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SummaryFour monoclonal antibodies (mAbs) were produced binding to four nonoverlapping epitopes on the superantigen staphylococcal enterotoxin B (SEB). The mAbs were tested for their ability to detect SEB bound to major histocompatibility complex (MHC) class II, to inhibit SEB binding to MHC class II, to inhibit SEB stimulation of T cell hybridomas, to bind to various nonfunctional mutants of SEB, and to capture and present SEB and its mutants to T cells in the absence of MHC class II. We concluded that two mAbs, B344 and B327, bound to epitopes not required for superantigen function, one mAb, 2B33, blocked an MHC interaction site on SEB, and the fourth mAb, B87, blocked the T cell recognition site on SEB. Moreover, two mAbs (B344 and 2B33) were capable of presenting SEB, although much less efficiently than APC, to CD4-but not CD4 § T cell hybridomas. The results confirm the functional domains on SEB originally defined by mutation and show that MHC class II is not always an essential component of the superantigen ligand.S taphylococcus aureus produces a set of exotoxin superantigens that cause food poisoning and toxic shock in man and rapid weight loss in mice sometimes leading to death (1-5). As superantigens these proteins bind to MHC class II molecules and activate a large set ofT cells in a V/3-specific fashion (6-12). This T cell stimulation and the accompanying massive release of lymphokines appear to play an essential role in the toxicity of these proteins (13,14).Although the amino acid sequences of the staphylococcal toxins are related, each has a unique V~ specificity. For example, in mice staphylococcal enterotoxin B (SEB) 1 stimulates T cells bearing V~7, 8.1, 8.2, and 8.3 (6, 10, 11), whereas SEA stimulates T cells bearing V/31, 3, 11, and 17a (10). We have identified mutants of SEB impaired either for binding to MHC or for interaction with ol/3 TCR-VBs (14). These mutations in SEB also eliminated in vivo toxicity in mice. When mapped on the structure of SEB, these mutations indicated different sites on the SEB surface for orb TCR versus MHC interaction (15).In the current study we have confirmed these conclusions using a set of four anti-SEB mAbs specific for four nonoveri Abbreviations used in this paper: CTM, complete tissue culture medium; FBS, fetal bovine serum; SEB, staphylococcal enterotoxin B; F-SEB, fluoresceinated SEB. lapping epitopes on SEB. Two of these antibodies define an MHC and an c~/3 TCR-interaction site on SEB, whereas, the other two react with sites not involved in SEB superantigen activity. Moreover, we found that two of these mAbs could substitute for MHC class II in presentation of SEB to T cell hybridomas. Materials and MethodsCell Lines. Three T cell hybridomas were used in these studies, all derived from B10.BR mice. KS-6.1 (VB8.2+) and

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“…It is now clear that the host response to bacteria includes responses not only to classical antigenic peptides, but also to recently described molecules such as superantigens [14][15][16][17][18] and promiscuous peptides [19][20][21][22]. Superantigens are molecules capable of activating all T cells expressing certain Vii products; since they can bind directly to any MHC class II molecule, they do not require prior antigen uptake or processing and are capable of stimulating T cells when fixed antigen-presenting cells (APC) are used [23,24], The ReA-associated bacterium, Yersinia enterocolitica has been shown to possess superantigenic activity in mice [25]. Promiscuous peptides [ 19,22], unlike superantigens, can bind to most but not all DR alleles; unlike classical peptide antigens, they are able to stimulate naive T cells from non-exposed donors including umbilical cord blood (UCB) T cells, as recently shown in the case of the malaria parasite [20,[26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns

Chieco-Bianchi

Hedley

Weissensteiner

et al. 1995

Clinical and Experimental Immunology

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SUMMARYIn reactive arthritis (ReA) a specific T cell response to the triggering bacterial antigen is present in the synovial fluid, while in paired peripheral blood T cells the response is tnarkedly reduced. The proliferative response to ReA-associated bacteria in the peripheral blood of ReA patients was compared with that seen in the blood of healthy adults, who denied exposure to these mierobes. and in the umbilical cord blood of newborns, who have clearly not been exposed to bacterial antigen. Peripheral blood mononuelear cells (PBMC) from non-exposed adults and those from umbilical cord blood proliferated to ReA-associated bacteria, whilst little response was seen in ReA PBMC. The response was MHC class Il-restricted, required processing of the bacterial antigen, was seen in both CD45RO ' and CD45RA^ subsets, and was not oligoclonal. These T cell responses are similar to (hose previously demonstrated in non-exposed individuals to malaria, leishmania and trypanosoma antigen, and may reflect the existence of "naiural* T ceil immunity to ReA-associated bacteria. The lack of such responses in ReA peripheral blood may suggest that such 'natural' responses may restrict the dissemination or progression of infection.

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High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR

Cited by 378 publications

References 19 publications

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Monoclonal antibodies defining functional sites on the toxin superantigen staphylococcal enterotoxin B.

Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns

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High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR

Cited by 378 publications

References 19 publications

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Monoclonal antibodies defining functional sites on the toxin superantigen staphylococcal enterotoxin B.

Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection