Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction

Abstract

Full T-cell activation requires interaction between the costimulatory receptors B7-2 and CD28. By binding CD28, bacterial superantigens elicit harmful inflammatory cytokine overexpression through an unknown mechanism. We show that, by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the avidity between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using the same 12-aa β-strand-hinge-α-helix domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, areas remote from where these coreceptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces. Short B7-2 dimer interface mimetic peptides bind diverse superantigens, prevent superantigen binding to cellsurface B7-2 or CD28, attenuate inflammatory cytokine overexpression, and protect mice from lethal superantigen challenge. Thus, superantigens induce a cytokine storm not only by mediating the interaction between MHC-II molecule and T-cell receptor but also, critically, by promoting B7-2/CD28 coreceptor engagement, forcing the principal costimulatory axis to signal excessively. Our results reveal a role for B7-2 as obligatory receptor for superantigens. B7-2 homodimer interface mimotopes prevent superantigen lethality by blocking the superantigen-host costimulatory receptor interaction.superantigen | cytokine storm | costimulatory receptor | B7-2 dimer interfaceA s principal costimulatory receptor, CD28 is a critical regulator of the immune response (1-3). Expressed constitutively on T cells, CD28 is a homodimer that interacts with its B7 coligands, transducing the signal essential for an immediate T-cell response (2-5). CD28 coligand B7-2 (CD86) is expressed constitutively on antigen-presenting cells whereas B7-1 (CD80) is induced only later (5, 6); thus, B7-2/CD28 interaction regulates early antigen signaling (7,8).The inflammatory cytokine response is indispensable for protective immunity, yet bacterial and viral infections often elicit an exaggerated response ("cytokine storm") harmful to the host. Thus, superantigens from Staphylococcus aureus and Streptococcus pyogenes induce toxic shock by activating an immune response, orders of magnitude beyond that elicited by regular antigens. Superantigens exploit the main axis of T-cell activation by binding directly as intact proteins to most major histocompatibility class II (MHC-II) and T-cell receptor (TCR) molecules outside their antigen-binding domains, linking them and bypassing restricted presentation of conventional antigens that typically activate <1% of T cells, thereby activating up to 20 to 30% of T cells (9-11). Moreover, T-cell activation by superantigens requires their direct binding to CD28 (12), the second signaling molecule mandatory for T-cell activation, which results in massive induction of inflammatory cytokines that mediate toxic shock, including IL-2, IFN-γ, and TNF.Induction of human inflammatory cytokine gene expression by divergent superantigens is inhibited by a short p...

Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

“…Once again, our peptide mimetic of the -strand-hinge--helix domain in superantigens proved useful. Induction of inflammatory cytokine gene expression by anti-CD3 together with the soluble extracellular domain of B7-2, a model for joint signaling through the TCR and B7-2/CD28 costimulatory pathway, was inhibited by this peptide [17] . The observation that a superantigen mimetic peptide inhibits signaling dependent on B7-2 could be explained, on one hand, by the direct interaction of this peptide with CD28 that we had already demonstrated [13] , resulting in attenuation of CD28 signaling.…”

“…Our hunch was borne out by direct binding studies [17] . SEB bound selectively to the surface of cells transfected to express B7-2.…”

“…Indeed, SEB bound soluble B7-2 extracellular domain protein when either was immobilized, as judged by direct immunoassay or by surface plasmon resonance, and as the free proteins in solution, shown by microscale thermophoresis. As for CD28, the superantigen binds to B7-2 with micromolar affinity [17] . Mutation of two highly conserved residues in the -strand/hinge/-helix domain of SEB that are critical for binding of CD28 [13] , abrogated binding of SEB to cell-surface B7-2, demonstrating specificity.…”

CD169+ Macrophages Restrain Systemic Inflammation Induced by Staphylococcus aureus Enterotoxin A Lung Response

“…Binding of S. aureus enterotoxins to molecules other than MHC II have been previously reported. In particular, the costimulatory molecule CD28 and its ligand CD86 are crucial binding sites that enhance the severity of the inflammatory response triggered by S. aureus enterotoxin (47). Other binding sites for S. aureus enterotoxins have been reported, including MHC class I (48), digalactosylceramide on kidney proximal tubular cells (49), and Gp130 receptor on adipocytes (50).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 1)

“…Вторым сигналом активации Т-клеток являются поверхностные молекулы антигенпрезентирую-щей клетки и Т-лимфоцита. Показано, что в су-перантиген-индуцированной активации Т-клеток происходит взаимодействие LFA-1 Т-лимфоцита с молекулой адгезии ICAM-1 антигенпрезентиру-ющей клетки и CD28 Т-лимфоцита с костимули-рующей молекулой CD80 антигенпрезентирующей клетки [36,38]. Данное взаимодействие приводит к активации митоген-активируемой протеинкиназы (mitogen-activated protein kinase -МАРК), внекле-точной регулируемой киназы (extracellular signal regulated kinase -ERK) и с-Jun N-терминальной киназы (c-Jun N-terminal kinase -JNK), предо-пределяя активацию транскрипционных факторов NF-κB, NF-AT и AP-1 [34,50].…”