Immature dendritic cells convert anergic nonregulatory T cells into Foxp3- IL-10+ regulatory T cells by engaging CD28 and CTLA-4

Eur J Immunol. 2015 Feb;45(2):480-91. doi: 10.1002/eji.201444991. Epub 2014 Dec 2.

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(+) 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.

Keywords: CD28; CTLA-4; Dendritic cell; T-cell anergy; Treg cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / genetics*
  • CD28 Antigens / immunology
  • CTLA-4 Antigen / genetics*
  • CTLA-4 Antigen / immunology
  • Cell Communication
  • Cell Differentiation
  • Clonal Anergy*
  • Coculture Techniques
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Early Growth Response Protein 2 / genetics
  • Early Growth Response Protein 2 / immunology
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / immunology
  • Gene Expression Regulation / immunology
  • Interleukin-10 / genetics*
  • Interleukin-10 / immunology
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / immunology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / pharmacology

Substances

  • CD28 Antigens
  • CTLA-4 Antigen
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IL10 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Transforming Growth Factor beta
  • Interleukin-10