CTLA4-Ig restores rejection of MHC class-II mismatched allografts by disabling IL-2-expanded regulatory T cells

Am J Transplant. 2012 Sep;12(9):2313-21. doi: 10.1111/j.1600-6143.2012.04184.x. Epub 2012 Jul 3.

Abstract

Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS(+) Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • CD28 Antigens / metabolism
  • Graft Rejection / immunology*
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Testing
  • Immunoconjugates / administration & dosage*
  • Interleukin-2 / administration & dosage*
  • Interleukin-2 / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • CD28 Antigens
  • Histocompatibility Antigens Class II
  • Immunoconjugates
  • Interleukin-2
  • Abatacept