CTLA-4 differentially regulates T cell responses to endogenous tissue protein versus exogenous immunogen.
CTLA-4 is critical to the regulation of CD4 T cell homeostasis in vivo. However, whether CTLA-4 regulates responses to both self and foreign proteins is not clear. We have directly compared the role of CTLA-4 in controlling T cell responses to the same protein presented as an endogenous tissue Ag vs a foreign immunizing Ag. We show that CTLA-4 only modestly reduces responses to Ag administered with adjuvant, but dramatically inhibits responses to the same Ag expressed transgenically as a tissue self protein. The critical consequence of CTLA-4 engagement is to inhibit T cell accumulation in the local lymph node draining the Ag-bearing tissue, and failure of this control leads to the onset of autoimmune tissue destruction. Thus, CTLA-4 may preferentially dampen pathologic immune responses to self proteins while permitting protective immunity to foreign agents.
Walker
Lucy S K
LS
Department of Pathology, University of California, San Francisco 94143, USA. walkerl@itsa.ucsf.edu
Ausubel
Lara J
LJ
Chodos
Anna
A
Bekarian
Nyree
N
Abbas
Abul K
AK
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D002645:Chickens; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000473:pathology; D007114:Immunization; D018796:Immunoconjugates; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D011506:Proteins; D011994:Recombinant Proteins; D000069594:Abatacept; D009113:Muramidase