A molecular perspective of CTLA-4 function.
Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.
The FOCIS Center for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5K8.
Wendy A
WA
Teft
Mark G
MG
Kirchhof
Joaquín
J
Madrenas
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001693:Biological Transport, Active; D060908:CTLA-4 Antigen; D019281:Dimerization; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D018448:Models, Immunological; D008967:Molecular Biology; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020836:Protein Structure, Quaternary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D008024:Ligands