title: MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4).
abstract: One of the key downregulators of T cell activation is CD152 (CTLA-4). Mice genetically deficient in CD152 (cd152(-/-) mice) develop massive expansion of both CD4(+) and CD8(+) T cells as well as increased numbers of splenic Ig-secreting cells and serum Ig levels. To determine the dependence of the lymphoproliferation and B cell hyperactivity on MHC class II (MHCII), MHCII-deficient (mhcii(-/-)) cd152(-/-) mice were generated. Compared to that in their mhcii(+/+) counterparts, expansion of CD4(+) cells in mhcii(-/-)cd152(-/-) mice was markedly attenuated. Nonetheless, expansion of CD8(+) cells was identical in both sets of mice, demonstrating that the effects of CD152 deficiency on CD4(+) cells can quantitatively be dissociated from those on CD8(+) cells, and pointing to a critical downregulatory role for CD152 in MHCII-independent CD8(+) cell activation in vivo. B cell hyperactivity also developed in mhcii(-/-)cd152(-/-) mice, albeit in a manner less rapid and less intense than that in their mhcii(+/+) counterparts, demonstrating an underlying MHCII-independent diathesis to B cell dysregulation and pointing to a critical downregulatory role for CD152 in MHCII-independent B cell activation in vivo. When human DQ8 was introduced as a transgene into mhcii(-/-)cd152(-/-) mice, B cell hyperactivity was restored to levels observed in mhcii(+/+)cd152(-/-) mice, pointing to a critical downregulatory role for CD152 in MHCII-dependent B cell activation in vivo superimposed upon its downregulatory role on MHCII-independent B cell activation.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. stohl@usc.edu
authors.forename: William
authors.initials: W
authors.lastname: Stohl
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000949:Histocompatibility Antigens Class II