New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Dong Zhang, Wei Yang, Nicolas Degauque, Yan Tian, Allison Mikita, Xiao Zheng Xin

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and healthy humans, 1% to 5% of αβ 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.

Original languageEnglish
Pages (from-to)4071-4079
Number of pages9
JournalBlood
Volume109
Issue number9
DOIs
StatePublished - 1 May 2007
Externally publishedYes

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