Submitted May 14, 2008
Accepted September 12, 2008
CD4+CD25+T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses
Nirupama D. Verma, Karren M. Plain, Masaru Nomura, Giang T. Tran, Catherine Robinson, Rochelle Boyd, Suzanne J. Hodgkinson, and Bruce M Hall*
Faculty of Medicine, The University of New South Wales, Eveleigh, NSW, Australia
Faculty of Veterinary Science, University of Sydney, Camden, NSW, Australia
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan
* Corresponding author; email: b.hall{at}unsw.edu.au.
CD4+CD25+Foxp3+T cells are regulatory/suppressor cells (Treg) that include non-antigen(Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naive CD4+CD25+Treg develop into specific Tregs is unknown. Here, we generated adaptive Tregs by culture of naive CD4+CD25+Foxp3+T cells with alloAg and either IL-2 or IL-4. Within days, IL-2 enhanced IFN-
R and IL-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5R
and increased IFN- mRNA expression. Both IL-2 and IL-4 alloactivated CD4+CD25+Tregs within 3-4 days of culture had enhanced capacity to induce tolerance to specific donor but not to third party cardiac allografts. These hosts became tolerant as allografts functioned >250 days, with a physiological ratio of <10% CD4+CD25+Foxp3+T cells in the CD4+ population. CD4+CD25+T cells from tolerant hosts given IL-2 cultured cells had increased IL-5 and IFN-R mRNA. Those from hosts given IL-4 cultured cells had enhanced IL-5R mRNA expression and IL-5 enhanced their proliferation to donor but not third party alloAg. Thus, IL-2 and IL-4 activated alloAg-specific Tregs with distinct phenotypes that were retained in vivo. These findings suggested that Th1 and Th2 responses activate two pathways of adaptive Ag-specific Tregs that mediate transplant tolerance. We propose they be known as Ts1 and Ts2 cells.
