Immature dendritic cells convert anergic nonregulatory T cells into Foxp3−IL‐10+ regulatory T cells by engaging CD28 and CTLA‐4 |
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Authors: | Katrien Pletinckx Martin Vaeth Theresa Schneider Niklas Beyersdorf Thomas Hünig Friederike Berberich‐Siebelt Manfred B. Lutz |
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Affiliation: | 1. Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany;2. Institute of Pathology, University of Würzburg, Würzburg, Germany |
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Abstract: | 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, nonsuppressive IL‐10?Foxp3?CTLA‐4+CD25lowEgr2+ T cells could be converted into suppressive IL‐10+Foxp3?CTLA‐4+CD25highEgr2+ cells resembling type‐1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF‐β during anergy induction favored Foxp3+ Treg‐cell induction, while TGF‐β 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/α 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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Keywords: | CD28 CTLA‐4 Dendritic cell Treg cell T‐cell anergy |
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