Heterogeneity within T Cell Memory: Implications for Transplant Tolerance

Scott M Krummey,Mandy L Ford

doi:10.3389/fimmu.2012.00036

Abstract

Adaptive immunity in both mouse and man results in the generation of immunological memory. Memory T cells are both friend and foe to transplant recipients, as they are intimately involved and in many cases absolutely required for the maintenance of protective immunity in the face immunosuppression, yet from the evidence presented herein they clearly constitute a formidable barrier for the successful implementation of tolerance induction strategies in transplantation. This review describes the experimental evidence demonstrating the increased resistance of memory T cells to many distinct tolerance induction strategies, and outlines recent advances in our knowledge of the ways in which alloreactive memory T cells arise in previously untransplanted individuals. Understanding the impact of alloreactive memory T cell specificity, frequency, and quality might allow for better donor selection in order to minimize the donor-reactive memory T cell barrier in an individual transplant recipient, thus allowing stratification of relative risk of alloreactive memory T cell mediated rejection, and conversely increase the likelihood of successful establishment of tolerance. However, further research into the molecular and cellular pathways involved in alloreactive memory T cell-mediated rejection is required in order to design new strategies to overcome the memory T cell barrier, without critically impairing protective immunity.

Highlights

A recent study by Katsikis et al found that CD8+ memory T cells derived from adoptively transferred cells required CD28mediated costimulation for optimal recall responses in a model of bacterial infection (Borowski et al, 2007). These findings suggest that under certain circumstances, memory T cells may depend on CD28 and/or CD154 mediated costimulation in order to generate optimum secondary recall responses
We recently showed in a murine model of experimental transplantation that treatment with anti-VLA-4 monoclonal antibodies synergized with costimulatory blockade in inhibiting allograft rejection mediated by donor-reactive memory T cells (Kitchens et al, 2011a)
When administered as part of a regimen consisting of CTLA-4 Ig (CD28 blockade) and sirolimus, CD2 adhesion molecule blockade resulted in renal allograft survival beyond the duration of treatment (>90 days) in five out of eight non-human primate renal allograft recipients (Weaver et al, 2009). These results provided the experimental foundation for the translation of alefacept, which is currently FDA approved for use in plaque psoriasis, as an adjunct therapy to be used in combination with CD28 blockers such as belatacept to inhibit donor-reactive memory T cell responses in transplantation

Summary

Introduction

Perhaps the most well-studied of example of the memory T cell barrier is the observed resistance of donor-specific www.frontiersin.org memory T cells, elicited either by exposure to donor antigens or viral pathogens, to tolerance induction via CD40 and CD28 costimulation blockers (Pantenburg et al, 2002; Valujskikh et al, 2002; Zhai et al, 2002; Adams et al, 2003). Numerous studies have demonstrated that blockade of these costimulatory pathways during transplantation are highly effective in tolerizing naïve donor-reactive T cells and lead to prolonged graft survival in both murine and non-human primate models (Linsley et al, 1992; Larsen et al, 1996; Kirk et al, 1997).

Results

Conclusion