CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy.
The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.
Chambers
C A
CA
University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Kuhns
M S
MS
Egen
J G
JG
Allison
J P
JP
D000069594:Abatacept; D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D017635:Clonal Anergy; D016207:Cytokines / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D018796:Immunoconjugates; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics; D046911:Macromolecular Substances; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D046911:Macromolecular Substances; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept