Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology

Abstract

Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology. In this article, we demonstrate mice treated with a single dose of abatacept 8 h post SEB exposure had reduced pathology compared with control SEB-exposed mice. SEB-exposed mice showed significant reductions in body weight between days 4 and 9, whereas mice exposed to SEB and also treated with abatacept showed no weight loss for the duration of the study, suggesting therapeutic mitigation of SEB-induced morbidity. Histopathology and magnetic resonance imaging demonstrated that SEB mediated lung damage and edema, which were absent after treatment with abatacept. Analysis of plasma and lung tissues from SEB-exposed mice treated with abatacept demonstrated significantly lower levels of IL-6 and IFN-γ (p < 0.0001), which is likely to have resulted in less pathology. In addition, exposure of human and mouse PBMCs to SEB in vitro showed a significant reduction in levels of IL-2 (p < 0.0001) after treatment with abatacept, indicating that T cell proliferation is the main target for intervention. Our findings demonstrate that abatacept is a robust and potentially credible drug to prevent toxic effects from SEB exposure.

Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation

“…Given structural similarities between SEB and the SARS-CoV-2 S protein SAg motif, there is potential for cross-reactivity of these immunoglobins, which may, in part, explain the response of MIS-C cases to IVIG. Other Food and Drug Administration-approved antiinflammatory drugs tested in models of SEB TSS may also be effective, including CTLA4-Ig which can inhibit CD28 costimulation (32), and the mammalian target of rapamycin (mTOR) inhibitor rapamycin (33), which is already in use for COVID-19. In addition, humanized monoclonal anti-SEB Abs (34,35) could be of potential therapeutic benefit in MIS-C patients.…”

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations

“…Given structural similarities between SEB and the S protein SAg motif, there is potential for cross-reactivity of these immunoglobins, explaining at least in part the response of MIS-C cases to IVIG. Other FDA-approved anti-inflammatory drugs tested in models of SEB TSS may also be effective, including CTLA4-Ig which can inhibit CD28 co-stimulation (30), and the mTOR inhibitor rapamycin (31), which is already in use for COVID-19. In addition, humanized monoclonal anti-SEB Abs have been described (32) that could also be of potential therapeutic benefit in MIS-C patients.…”

Lack of cytomegalovirus (CMV)-specific cell-mediated immune response using QuantiFERON-CMV assay in CMV-seropositive healthy volunteers: fact not artifact

“…In addition, discordant CMV+ QF− individuals show not only reduced specific immunity to CMV, but also against superantigen SEA + SEB. Both toxins bind in a non-specific manner to MHC class II on antigen presentation cells as well as to the T-cell antigen receptor of CD4+ T cells, producing a massive proliferation of T cells www.nature.com/scientificreports www.nature.com/scientificreports/ and release of proinflammatory cytokines 24,25 . Therefore, the significantly lower proliferation of CD4+ T cells with superantigen that we observed in CMV+ QF− individuals would support the role of CD4+ T cells in the discordance in CMV-seropositive individuals.…”