Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-beta 1 null mouse.
TGF-beta 1 null (TGF-beta1-/-) mice die at 3-4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-beta 1-/- mice, we generated TGF-beta 1-/- mice in the genetic background of beta 2-microglobulin deficiency (beta 2M-/-). TGF-beta 1-/-;beta 2M-/- mice had improved survival compared with TGF-beta 1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-beta 1-/- mice. In vivo depletion of CD8+ T cells in TGF-beta 1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-beta 1-/-;beta 2M-/- mice was also lower than that in TGF-beta 1-/- mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-beta 1-/-;beta 2M-/- mice, when compared with that in TGF-beta 1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-beta 1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-beta 1-/- mice.
Kobayashi
S
S
Functional Genomics Unit, Gene Targeting Facility, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
Yoshida
K
K
Ward
J M
JM
Letterio
J J
JJ
Longenecker
G
G
Yaswen
L
L
Mittleman
B
B
Mozes
E
E
Roberts
A B
AB
Karlsson
S
S
Kulkarni
A B
AB
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003433:Crosses, Genetic; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005804:Genes, Lethal / Q000276:immunology*; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D019891:Leukopoiesis / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics*; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001613:beta 2-Microglobulin