title: Role of CD28 in fatal autoimmune disorder in scurfy mice.
abstract: Scurfy mice develop CD4 T-cell-mediated lymphoproliferative disease leading to death within 4 weeks of age. The scurfy mutation causes loss of function of the foxp3 gene (foxp3(sf)), which is essential for development and maintenance of naturally occurring regulatory CD4 T cells (nTregs). In humans, mutations of the foxp3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). In most patients with IPEX and also in scurfy mice, T cells show hyperreactivity and levels of Th1- and Th2-associated cytokines are substantially elevated. We report that removal of CD28 expression rescued scurfy mice from early death. Longer-term surviving CD28-deficient scurfy mice still had lymphoproliferative disorder, but their CD4 T cells showed decreased interferon-gamma and no sign of interleukin-4 or interleukin-10 hyperproduction. Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially improved the survival of scurfy mice by blocking effector T-cell differentiation. These data support the hypothesis that CD28-B7 interactions play a critical role in the etiology of lethal autoimmune disease in scurfy mice by stimulating the differentiation of antigen-activated naive T cells into effector T cells.
authors.affiliation: Immunotherapy Center, Medical College of Georgia, Augusta, USA.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Chandler
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Seki
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takezaki
authors.forename: David J
authors.initials: DJ
authors.lastname: Kahler
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: Makio
authors.initials: M
authors.lastname: Iwashima
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005804:Genes, Lethal; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology / Q000401:mortality / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma