Tyrosine-mediated inhibitory signals contribute to CTLA-4 function in vivo.
The ability of CTLA-4 to inhibit T cell activation may be either negatively or positively regulated by a critical tyrosine at position 201 (Y201) within the CTLA-4 cytoplasmic domain. By binding to the clathrin-associated adaptor complex AP-2 and inducing endocytosis, Y201 reduces the amount of CTLA-4 on the cell surface, thereby down-regulating CTLA-4 inhibitory function. Alternatively, Y201 may function to transmit CTLA-4 inhibitory signals, perhaps through binding to intracellular proteins that oppose TCR- and/or CD28-induced signal transduction. Results from studies performed in vitro have cast doubt on whether this second mechanism contributes significantly to CTLA-4 function. In order to determine if a role existed for Y201 in mediating CTLA-4 inhibitory signaling in vivo, we studied lymphocyte activation and homeostasis in CTLA-4(-/-) mice that were reconstituted with a transgenic CTLA-4 receptor in which Y201 was mutated to valine (Y201V/CTLA-4(-/-)). We found that despite augmented levels of CTLA-4 on the cell surface of T cells, Y201V/CTLA-4(-/-) mice developed a lymphoproliferative syndrome characterized by lymphadenopathy and the accumulation of T cells that secreted IL-4. Mutant T cells exhibited increased cell division when treated with suboptimal doses of mitogenic stimuli in vitro. These results demonstrate that in addition to down-modulating CTLA-4 expression on the cell surface of T cells, the Y201 residue also functions to transmit CTLA-4 inhibitory signals in vivo. Elucidating the biochemical pathways downstream of Y201 will be important for a full understanding of the molecular basis for CTLA-4 function.
Yi
Lou Ann
LA
Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Hajialiasgar
Soheila
S
Chuang
Ellen
E
D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D060908:CTLA-4 Antigen; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D003433:Crosses, Genetic; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017354:Point Mutation / Q000235:genetics / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014443:Tyrosine / Q000235:genetics / Q000502:physiology*; D000099192:CD69 Antigens
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D007371:Interferon-gamma; D015847:Interleukin-4; D019041:L-Selectin; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D015375:Receptors, Interleukin-2; D014443:Tyrosine; D000099192:CD69 Antigens; C556707:Ctla4 protein, mouse