Project title: CD8+CD28neg T cells, a threat to TRANSPLANTATION?
Kidney transplantation is the treatment of choice for End-Stage Renal dysfunction from patient survival perspective as well as from an economical point-of-view. Preventing the occurrence of acute rejection is not anymore an issue. However, minimal success had been obtained to prevent late chronic rejection and current immunosuppressive drugs are associated with increased infections, viral reactivations and malignancies. It is thus critical to design innovative strategies to control the pathogeneic cells involved in chronic rejection.
We and others have accumulated evidences that the direct pathway of allorecognition is functional months after transplantation and that the composition of CD8 T cell subsets is modified in patients with chronic antibody-mediated rejection (CABMR). The frequency of CD8+CD28- T cells is increased in patients with biopsy-proven CABMR (Baeten et al JASN 2006). We have also reported, in a large cohort of kidney transplant recipient with a stable graft function for more than 5 years, that one third of the patients exhibit strong alterations of their TCR Vβ repertoire (Miqueu et al Eur J Immunol 2010) that are associated with an expansion of Effector Memory cells re-expressing CD45RA (EMRA) (Yap et al JASN 2014) despite the stability of their kidney graft function. Patients with an expansion of TEMRA CD8 T cells exhibit a 2-fold higher risk of kidney dysfunction (Yap et al JASN 2014). These results have been confirmed in a new cohort of kidney transplant recipients analyzed 12-month post-transplantation (unpublished data).
Targeting costimulatory molecules has emerged as a promising alternative to control the alloresponse against the graft while promoting tolerance mechanisms and preventing adverse effects of current IS drugs. For instance, the disruption of CD28 – CD80/86 pathway using Belatacept (CTLA4-Ig) had been recently approved for kidney transplantation. However, the introduction of Belatacept has lead to the identification of costimulation blockade resistant patients in which a sizable frequency of CD8+CD28- T cells could be evidenced. The loss of CD28 expression in T cells could be driven by repeated antigen stimulation leading to the generation of highly antigen-experienced CD8+CD28- T cells. CD8+CD28- T cells have been shown to exhibit polyfunctional cells including multiple cytokines secretion and high level of cytotoxic molecules (PERF and GZM-b) in the context of alloreactive assays.
Collectively, these results highlight that pre-existing or neo-formed pathogeneic CD8+CD28- T cells are a barrier for long-term graft acceptance that cannot be control by actual IS drugs nor by the newly developed costimulation blockade drugs.
The aim of the project is to characterize the development of pathogeneic CD8+CD28- T cells after kidney transplantation and to evaluate in humanized mouse model the ability to control their immune function by metabolic interferences. The project is divided into 3 tasks
- Task #1. To investigate the adaptation of the metabolism of CD8 T cell subsets after kidney transplantation
- Task #2. To develop humanized mouse models to study CD8+CD28- T cells pathogenicity
- Task #3. To test the ability of metabolic interferences to control the immune response of CD8+CD28- T cells in preclinical models.