Costimulation of T cells by OX40, 4-1BB, and CD27.
Costimulatory signals have been defined as signals brought about by ligation of membrane bound molecules that synergize with, or modify, signals provided when the T cell receptor engages peptide-MHC complexes. In large part, costimulatory signals are essential for many facets of a T cell response, and the general rule is that without these signals, a T cell is ineffective and may often succumb to death or become unresponsive. Until recently, costimulation has been dominated by studies of the Ig superfamily member, CD28, a constitutively expressed molecule that is required to initiate a majority of T cell responses. However, growing evidence over the past few years has now shown that several members of the TNFR family, OX40 (CD134), 4-1BB (CD137), and CD27, are equally important to the effective generation of many types of T cell response. In contrast to CD28, these molecules are either induced or highly upregulated on the T cell surface a number of hours or days after recognition of antigen, and appear to provide signals to allow continued cell division initially regulated by CD28 and/or to prevent excessive cell death several days into the response. An argument can be made that these molecules control the absolute number of effector T cells that are generated at the peak of the immune response and dictate the frequency of memory T cells that subsequently develop. The exact relationship between OX40, 4-1BB, and CD27, is at present unknown, including whether these molecules act together, or sequentially, or control differing types of T cell response. This review will focus on recent studies of these molecules and discuss their implications.
Croft
Michael
M
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA. mick@liai.org
D000818:Animals; D015703:Antigens, CD; D053282:CD27 Ligand; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology*; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; C505772:Cd70 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C505714:TNFRSF9 protein, human; C505717:Tnfrsf4 protein, mouse; C505715:Tnfrsf9 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9