Vβ repertoire in rats and implications for endogenous superantigens
27
Citation
24
Reference
10
Related Paper
Abstract:
Abstract Endogenous superantigens of mice, encoded by mammary tumor virus proviral integrants, induce intrathymic deletion of entire T cell populations that express specific V β gene products, a phenomenon proposed to be important in self‐tolerance and prevention of toxic responses to exogenous microbial superantigens. Evidence for the presence of V β selecting/deleting endogenous superantigens in other species is lacking. We report here that rats do not exhibit endogenous superantigen‐induced V β clonal deletions despite their strong response to bacterial superantigens. These findings indicate that endogenous superantigens are not obligatory in V β repertoire shaping.Keywords:
Superantigen
Sequencing of the T cell receptor (TCR) repertoire is a powerful tool for deeper study of immune response, but the unique structure of this type of data makes its meaningful quantification challenging. We introduce a new method, the Gamma-GPD spliced threshold model, to address this difficulty. This biologically interpretable model captures the distribution of the TCR repertoire, demonstrates stability across varying sequencing depths, and permits comparative analysis across any number of sampled individuals. We apply our method to several datasets and obtain insights regarding the differentiating features in the T cell receptor repertoire among sampled individuals across conditions. We have implemented our method in the open-source R package powerTCR.
clone (Java method)
Immune receptor
Cite
Citations (19)
Superantigen
Cite
Citations (5)
The Centers for Disease Control and Prevention (CDC) and others reported that methicillin-resistant S. aureus (MRSA) are significant causes of serious human infections, including pulmonary illnesses. We investigated the role played by superantigens in lung-associated lethal illness in rabbits.A rabbit model was established to investigate the potential role played by superantigens, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC), and toxic shock syndrome toxin-1 (TSST-1). Rabbits received intrabronchial community-associated (CA) MRSA strains USA200 (TSST-1(+)), MW2 (SEC(+)), c99-529 (SEB(+)), or purified superantigens. Some rabbits were preimmunized against superantigens or treated with soluble high-affinity T cell receptors (Vβ-TCR) to neutralize SEB and then challenged intrabronchially with CA-MRSA or superantigens.Rabbits challenged with CA-MRSA or superantigens developed fatal, pulmonary illnesses. Animals preimmunized against purified superantigens, or treated passively with Vβ-TCRs and then challenged with CA-MRSA or superantigens, survived. Lung histological analysis indicated that nonimmune animals developed lesions consistent with necrotizing pneumonia after challenge with CA-MRSA or purified superantigens. Superantigen-immune animals or animals treated with soluble Vβ-TCRs did not develop pulmonary lesions.Superantigens contribute to lethal pulmonary illnesses due to CA-MRSA; preexisting immunity to superantigens prevents lethality. Administration of high-affinity Vβ-TCR with specificity for SEB to nonimmune animals protects from lethal pulmonary illness resulting from SEB(+) CA-MRSA and SEB.
Superantigen
Cite
Citations (66)
ABSTRACT Endogenous superantigen-mediated thymic negative selection resulted in a paucity of mature T cells bearing T-cell receptor (TCR) Vβ8 in the periphery. Consequently, the magnitude of immune response to exogenous superantigen staphylococcal enterotoxin B, which activates TCR Vβ8 + T cells, was significantly reduced and conferred protection from superantigen-induced mortality.
Superantigen
Clonal deletion
Cite
Citations (11)
AbstractMicrobial superantigens represent a group of molecules that is able to cause massive activation of the host immune system. Human diseases originating from superantigen-secreting bacterial agents are characterized by shock, which continues to pose major health problems. Presently, the treatment of superantigen-mediated infections is limited to the administration of antibiotics and handling of the state of shock. However, the development of multiple antibiotic-resistant, superantigen-producing bacterial strains increases the threat of these infections, and prompts researchers to better understand and treat disease states in which exposure to superantigens is at least partly responsible for the outcome. In the past decade, significant understanding has been achieved regarding the molecular mechanisms of superantigen-host interactions. Based on this understanding, a variety of promising strategies directed against superantigens have been developed. In this review, we discuss some of these strategies, as well as the potential for therapeutic applications of superantigens for the benefit of the host.
Superantigen
Toxic shock syndrome
Cite
Citations (9)
Abstract Endogenous superantigens of mice, encoded by mammary tumor virus proviral integrants, induce intrathymic deletion of entire T cell populations that express specific V β gene products, a phenomenon proposed to be important in self‐tolerance and prevention of toxic responses to exogenous microbial superantigens. Evidence for the presence of V β selecting/deleting endogenous superantigens in other species is lacking. We report here that rats do not exhibit endogenous superantigen‐induced V β clonal deletions despite their strong response to bacterial superantigens. These findings indicate that endogenous superantigens are not obligatory in V β repertoire shaping.
Superantigen
Cite
Citations (27)
Superantigens cross-link the MHC II molecule on accessory cells with the Vβ region of the T cell receptor (TCR). In this study, we compared the capacity of established superantigens for inducing cytokine release. The experimental protocol was generated to answer the question whether all superantigen effects are transmitted by the MHC/TCR cross-linkage and induce mainly a T cell response. We found that TSST-1, ExFTA, and SEC3 differed from all other superantigens tested because they stimulated a stronger monokine release. T cell proliferation after challenge with these superantigens was mainly mediated by a cytokine pathway and not by the cross-linkage of MHC and TCR. For the other superantigens, we were able to demonstrate that major immunomodulatory effect is mediated by the superantigen bridge. With the exception of these three superantigens, the proliferative response of superantigens correlated with their Vβ specificity. Interleukin-1 (IL-1) and IL-6 were induced in monocytes by all superantigens, whereas tumor necrosis factor-α (TNF-α) was induced in T cells and by some superantigens, also in monocytes. IL-2 was always induced by the superantigen bridge, whereas interferon-γ (IFN-γ) was also induced indirectly by monokines. Collectively, our results indicate that not all superantigens are suitable for investigating superantigen-specific effects, as they show indirect (mitogenic) side effects. Observations for an individual superantigen are, therefore, not transferable to all other superantigens.
Superantigen
Cite
Citations (9)
Superantigen
Toxic shock syndrome
Cite
Citations (0)
Abstract The species Staphylococcus aureus harbors 19 superantigen gene loci, six of which are located in the enterotoxin gene cluster (egc). Although these egc superantigens are far more prevalent in clinical S. aureus isolates than non-egc superantigens, they are not a prominent cause of toxic shock. Moreover, neutralizing Abs against egc superantigens are very rare, even among carriers of egc-positive S. aureus strains. In search of an explanation, we have tested two non-exclusive hypotheses: 1) egc and non-egc superantigens have unique intrinsic properties and drive the immune system into different directions and 2) egc and non-egc superantigens are released by S. aureus under different conditions, which shape the immune response. A comparison of three egc (SEI, SElM, and SElO) and three non-egc superantigens (SEB, SElQ, and toxic shock syndrome toxin-1) revealed that both induced proliferation of human PBMC with comparable potency and elicited similar Th1/Th2-cytokine signatures. This was supported by gene expression analysis of PBMC stimulated with one representative superantigen from each group (SEI and SEB). They induced very similar transcriptional changes, especially of inflammation-associated gene networks, corresponding to a very strong Th1- and Th17-dominated immune response. In contrast, the regulation of superantigen release differed markedly between both superantigen groups. Egc-encoded proteins were secreted by S. aureus during exponential growth, while non-egc superantigens were released in the stationary phase. We conclude that the distinct biological behavior of egc and non-egc superantigens is not due to their intrinsic properties, which are very similar, but caused by their differential release by S. aureus.
Superantigen
Toxic shock syndrome
Cite
Citations (63)
Superantigen
Chronic Rhinosinusitis
Cite
Citations (6)