CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation.
CTLA-4 is constitutively expressed by CD4(+)CD25(+)Foxp3(+) Treg but its precise role in Treg function is not clear. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4-deficient Treg have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. Conditional deletion of CTLA-4 in Foxp3(+) T cells disrupts immune homeostasis in vivo but the immune processes disrupted by CTLA-4 deletion have not been determined. We demonstrate that Treg expression of CTLA-4 is essential for Treg control of lymphopenia-induced CD4 T-cell expansion. Despite IL-10 expression, CTLA-4-deficient Treg were unable to control the expansion of CD4(+) target cells in a lymphopenic environment. Moreover, unlike their WT counterparts, CTLA-4-deficient Treg failed to inhibit cytokine production associated with homeostatic expansion and were unable to prevent colitis. Thus, while Treg developing in the absence of CTLA-4 appear to acquire some compensatory suppressive mechanisms in vitro, we identify a non-redundant role for CTLA-4 in Treg function in vivo.
Sojka
Dorothy K
DK
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Hughson
Angela
A
Fowell
Deborah J
DJ
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D000954:Antigens, Surface / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000276:immunology / Q000517:prevention & control; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000954:Antigens, Surface; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; C499308:Rag2 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D014364:Tryptophan; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse