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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4594-4601.
Prepublished online as a Blood First Edition Paper on March 11, 2004; DOI 10.1182/blood-2003-08-2897.
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Submitted August 25, 2003
Accepted February 18, 2004
CD28 disruption exacerbates inflammation in Tgf- 1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-1
Mizuko Mamura, WoonKyu Lee, Timothy J Sullivan, Angelina Felici, Anastasia L Sowers, James P Allison, and John J Letterio*
Lab of Cell Regulation and Carcinogenesis, National Institutes of Health, CCR, Bethesda, MD, USA
Lab of Mammalian Genes and Development, National Institutes of Health, Bethesda, MD, USA
Cancer Research Laboratory, Howard Hughes Medical Institute, Berkeley, CA, USA
Lab of Molecular Biology, National Institutes of Health, CCR, Bethesda, MD, USA
* Corresponding author; email: wklee{at}mail.nih.gov.
Tgf- 1-/- mice develop a progressive, lethal inflammatory syndrome, but mechanisms leading to spontaneous activation of Tgf-1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-1-/- mice and 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-1-/- mice, and display characteristic expression CTLA-4, GITR,  E7 integrin, and Foxp3. Adoptive transfer of Tgf-1-/- splenocytes to Tgf-1+/+; Rag2 -/- mice induced an autoimmune inflammatory disease with similar features of the Tgf-1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-1-/- CD4+CD25+ T cells from donor splenocytes. Co-transfer of Tgf-1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2 -/- recipients of CD25+-depleted Tgf-1-/- spleen and lymph node cells, but suppression was incomplete when compared to Tgf-1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous TGF-1 expression, and that autocrine TGF-1 expression is not essential for these cells to suppress inflammation in vivo.
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