CD28 disruption exacerbates inflammation in Tgf-beta1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1.
Tgf-beta1-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-beta1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-beta1-/- mice, and we link this increase in severity to a reduction in the number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf-beta1-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), alpha(E)beta7 integrin, and Foxp3. Adoptive transfer of Tgf-beta1-/- splenocytes to Tgf-beta1+/+/Rag2-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-beta1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-beta1-/- CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- beta1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf-beta1-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-beta1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-beta1 (TGF-beta1) expression and that autocrine TGF-beta1 expression is not essential for these cells to suppress inflammation in vivo.
Mamura
Mizuko
M
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bldg 41, 41 Library Drive/MSC 5055, Bethesda, MD 20892-5055, USA.
Lee
WoonKyu
W
Sullivan
Timothy J
TJ
Felici
Angelina
A
Sowers
Anastasia L
AL
Allison
James P
JP
Letterio
John J
JJ
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics*; D015704:CD4 Antigens / Q000235:genetics; D002469:Cell Separation; D007165:Immunosuppression Therapy; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1
D018106:CD28 Antigens; D015704:CD4 Antigens; D015375:Receptors, Interleukin-2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1