title: CD28 Costimulation: From Mechanism to Therapy.
abstract: 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 might 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.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA. Electronic address: jonathan.esensten@ucsf.edu.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Esensten
authors.affiliation: Division of Rheumatology, Department of Medicine, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Ynes A
authors.initials: YA
authors.lastname: Helou
authors.affiliation: Department of Chemistry, Purdue Center for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Chopra
authors.affiliation: Division of Rheumatology, Department of Medicine, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA. Electronic address: jeff.bluestone@ucsf.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D006706:Homeostasis; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D008213:Lymphocyte Activation; D051379:Mice; D058990:Molecular Targeted Therapy; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept