Differential regulation of motility and immune synapses by CD28/ CTLA-4 costimulation in effector and regulatory T cells

  • Nahzli Dilek
  • Nicolas Poirier
  • Philippe Hulin
  • Gilles Blancho
  • Bernard Vanhove
Open Access
Poster presentation
  • 822 Downloads

Keywords

Treg Cell Stop Signal Synapse Formation Calcium Flux Tolerance Induction 

Background

We have previously shown that antagonist anti-CD28 antibodies block CD28/CD80-86 costimulation without perturbation of the CTLA-4/CD80-86 inhibitory pathway and favor tolerance induction by increasing Treg suppression in a CTLA-4 dependent manner. Since CTLA-4 is transducing signals that block the TCR-STOP signal, described to allow for T cell arrest and formation of immune synapses, we hypothesized that CTLA-4 might play a major role in the mechanism of action of anti-CD28 antibodies by regulating T cell motility and synapses formation.

Materials, methods and results

Here, we generated human CD4+CD25+CD127+ Teff and CD4+CD25highCD127lowFoxp3+ Treg cell lines and analyzed their behavior in contact with cognate APCs by live-cell dynamic microscopy in the presence of CD28 and CTLA-4 antagonists. CD28 blockade prevented formation of stable contacts between Teff and APCs (11.93 ± 1.175 vs 4.167 ± 1.191 min; p<0.05), increased Teff mobility (100.5 ± 6.032 vs 204.8 ± 17.54 µm; p<0.0001) and decreased cell activation measured by calcium flux (0.377 ± 0.028 vs 0.154 ± 0.024 calcium peaks/min; p<0.0001). In contrast, CD28 antagonists enhanced Treg/APC contacts (5.057 ± 0.866 vs 13.81 ± 1.104 min; p<0.0001) and increased calcium flux (0.486 ± 0.048 vs 0.677 ± 0.06 calcium peaks/min; p<0.05), resulting in an increase of Treg activation. The simultaneous blockade of CTLA-4 with antibodies or of CD80/86 with CTLA4Ig reversed some of these effects: it restored the STOP signal and reduced motility/velocity in Teff whereas it increased velocity in Treg and abolished Treg/APC contacts.

Conclusion

Our data shed light on the role of CD28 and CTLA-4 that act as a rheostat to differentially control Teff and Treg function and clarify the observations that selective CD28-blockade but not CD80/86 blockade reinforces Treg cell suppression in vitro.

Copyright information

© Dilek et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Nahzli Dilek
    • 1
    • 2
  • Nicolas Poirier
    • 1
    • 2
  • Philippe Hulin
    • 1
    • 2
  • Gilles Blancho
    • 1
    • 2
  • Bernard Vanhove
    • 1
    • 2
  1. 1.Institute of Transplantation Urology NephrologyUniversity of NantesNantesFrance
  2. 2.IMPACT INSERM platformNantesFrance

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