期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 45, 期 2, 页码 480-491出版社
WILEY
DOI: 10.1002/eji.201444991
关键词
CD28; CTLA-4; Dendritic cell; Treg cell; T-cell anergy
类别
资金
- Deutsche Forschungsgemeinschaft (DFG) [Transregio Sonderforschungsbereich 52 (TR52)]
Anergic T cells can survive for long time periods passively in a hyporesponsive state without obvious active functions. Thus, the immunological reason for their maintenance is unclear. Here, we induced peptide-specific anergy in T cells from mice by coculturing these cells with immature murine dendritic cells (DCs). We found that these anergic, non-suppressive IL-10(-)Foxp3(-)CTLA-4(+)CD25(low)Egr2(+)T cells could be converted into suppressive IL-10(+)Foxp3(-)CTLA-4(+)CD25(high)Egr2(+) cells resembling type-1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF-beta during anergy induction favored Foxp3(+) Treg-cell induction, while TGF-beta had little effect when added to the second stimulation. Expression of both CD28 and CTLA-4 molecules on anergic T cells was required to allow their conversion into Tr1-like cells. Suppressor activity was enabled via CD28-mediated CD25 upregulation, acting as an IL-2 sink, together with a CTLA-4-mediated inhibition of NFATc1/alpha activation to shut down IL-2-mediated proliferation. Together, these data provide evidence and mechanistical insights into how persistent anergic T cells may serve as a resting memory pool for Tr1-like cells.
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