T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding

Sánchez-Lockhart, Mariano; Rojas, Ana V.; Fettis, Margaret M.; Bauserman, Richard G.; Higa, Trissha R.; Miao, Hongyu; Waugh, Richard E.; Miller, Jim

doi:10.1371/journal.pone.0089263

Cited by 31 publications

(23 citation statements)

References 63 publications

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“…The dependence of superantigen mechanism of action on engagement of the B7-2 and CD28 homodimer interfaces raises the possibility that these domains function also in costimulatory signaling in the absence of superantigens and that this property has been exploited by the superantigen toxins. Indeed, the avidity of CD28 for B7-2 increases after TCR signaling, and mutations in the p1TA dimer interface domain of CD28 (12) mimic this change, suggesting that CD28/B7-2 avidity is regulated through the CD28 dimer interface (22).…”

Section: Discussionmentioning

confidence: 99%

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

Levy

Rotfogel

Hillman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

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

Levy

Rotfogel

Hillman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Follow up studies suggested that TCR signaling increased the avidity of CD28-CD80 interactions (Sanchez-Lockhart et al, 2014). Specifically, molecular dynamic simulations and site-directed mutagenesis experiments supported a model whereby the TCR signaling induced an increase in CD28 avidity as a consequence of reorientation of the CD28 dimer to engage in bivalent interactions with its ligand (Sanchez-Lockhart et al, 2014). As most studies to date lack insight into the ligand binding affinity of CD28 within the plasma membrane, the valency of CD28 binding warrants more investigation.…”

Section: Cd28 Structure and Ligand Bindingmentioning

confidence: 99%

CD28 Costimulation: From Mechanism to Therapy

et al. 2016

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Summary Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven with both successes and failures. Such real-world results may stem from multiple factors including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.

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“…Until now, the experimental structure of B7‐1:human CD28 (hCD28):(or B7‐2:hCD28) complex was not reported in the literature. Most of the efforts to understand the structures of B7:CD28 complexes were driven through molecular modeling and simulations . A recent molecular model of B7‐1:CD28 (Figure D) suggested that the key differences between the B7‐1:CD28 and B7‐1:CTLA‐4 complexes were mainly observed on the B7‐1 surface .…”

Section: Structures Of B7‐1 and Its Complexes With Ctla‐4 And Cd28mentioning

confidence: 99%

Targeting B7‐1 in immunotherapy

Chen

Okoye

Arutyunova

et al. 2019

Medicinal Research Reviews

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Modulation of T‐cell immune functions by blocking key immune checkpoint protein interactions using monoclonal antibodies (mAbs) has been an innovative immunotherapeutic strategy. T‐cells are regulated by different checkpoint proteins at the immunological synapse including the B7 ligands (B7‐1 or CD80 and B7‐2 or CD86), which is discussed in this review. These ligands are typically expressed on antigen presenting cells and interact with CD28 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4) receptors on T‐cells. Their interactions with CD28 trigger a costimulatory signal that potentiates T‐cell activation, function and survival in response to cognate antigen. In addition, their interactions with CTLA‐4 can also inhibit certain effector T‐cell responses, particularly in response to sustained antigen stimulation. Through these mechanisms, the balance between T‐cell activation and suppression is maintained, preventing the occurrence of immunopathology. Given their crucial roles in immune regulation, targeting B7 ligands has been an attractive strategy in cancer and autoimmunity. This review presents an overview of the essential roles of B7‐1, highlighting the therapeutic benefits of modulating this protein in immunotherapy, and reviewing earlier and state‐of‐the‐art efforts in developing anti‐B7‐1 inhibitors. Finally, we discuss the challenges facing the design of selective B7‐1 inhibitors and present our perspectives for future developments.

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T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding

Cited by 31 publications

References 63 publications

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

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

CD28 Costimulation: From Mechanism to Therapy

Targeting B7‐1 in immunotherapy

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