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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4071-4079. Prepublished online as a Blood First Edition Paper on December 29, 2006; DOI 10.1182/blood-2006-10-050625.
TRANSPLANTATION New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses1 Transplantation Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA; 2 Capital University of Medical Sciences, Beijing Friendship Hospital, Beijing, China
Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
ß T-cell receptor–positive (TCR+) T cells are CD4–CD8– (double-negative [DN]) T cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T cells to DN regulatory T cells. We showed that the converted DN T cells retained a stable phenotype after restimulation and that furthermore, the disappearance of cell-surface CD4 molecules on converted DN T cells was a result of CD4 gene silencing. The converted DN T cells were resistant to activation-induced cell death (AICD) and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen-specific manner. Perforin was highly expressed by the converted DN regulatory T cells and played a role in DN T-cell–mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection. 
