Immature dendritic cells convert anergic nonregulatory T cells into Foxp3- IL-10+ regulatory T cells by engaging CD28 and CTLA-4.
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(+) 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-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.
Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Katrien
K
Pletinckx
Martin
M
Vaeth
Theresa
T
Schneider
Niklas
N
Beyersdorf
Thomas
T
Hünig
Friederike
F
Berberich-Siebelt
Manfred B
MB
Lutz
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics* / Q000276:immunology; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D002450:Cell Communication; D002454:Cell Differentiation; D017635:Clonal Anergy; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
CD28; CTLA-4; Dendritic cell; T-cell anergy; Treg cell