title: CTLA-4 engagement acts as a brake on CD4+ T cell proliferation and cytokine production but is not required for tuning T cell reactivity in adaptive tolerance.
abstract: Adaptive tolerance is the physiologic down-regulation of T cell responsiveness in the face of persistent antigenic stimulation. In this study, we examined the role of CTLA-4 in this process using CTLA-4-deficient and wild-type TCR transgenic, Rag2(-/-), CD4(+) T cells transferred into a T cell-deficient, Ag-expressing host. Surprisingly, we found that the tuning process of adoptively transferred T cells could be induced and the hyporesponsive state maintained in the absence of CTLA-4. Furthermore, movement to a deeper state of anergy following restimulation in vivo in a second Ag-bearing host was also unaffected. In contrast, CTLA-4 profoundly inhibited late T cell expansion in vivo following both primary and secondary transfers, and curtailed IL-2 and IFN-gamma production. Removal of this braking function in CTLA-4-deficient mice following Ag stimulation may explain their lymphoproliferative dysregulation.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Manabu
authors.initials: M
authors.lastname: Inobe
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Schwartz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017252:CD3 Complex / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D010856:Columbidae; D045304:Cytochromes c / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007113:Immunity, Innate / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C485468:Cd3e protein, mouse; C556707:Ctla4 protein, mouse; D016207:Cytokines; D006131:Growth Inhibitors; D045304:Cytochromes c