title: Co-Stimulatory Blockade of the CD28/CD80-86/CTLA-4 Balance in Transplantation: Impact on Memory T Cells?
abstract: CD28 and CTLA-4 are prototypal co-stimulatory and co-inhibitory cell surface signaling molecules interacting with CD80/86, known to be critical for immune response initiation and regulation, respectively. Initial "bench-to-beside" translation, two decades ago, resulted in the development of CTLA4-Ig, a biologic that targets CD80/86 and prevents T-cell costimulation. In spite of its proven effectiveness in inhibiting allo-immune responses, particularly in murine models, clinical experience in kidney transplantation with belatacept (high-affinity CTLA4-Ig molecule) reveals a high incidence of acute, cell-mediated rejection. Originally, the etiology of belatacept-resistant graft rejection was thought to be heterologous immunity, i.e., the cross-reactivity of the pool of memory T cells from pathogen-specific immune responses with alloantigens. Recently, the standard view that memory T cells arise from effector cells after clonal contraction has been challenged by a "developmental" model, in which less differentiated memory T cells generate effector cells. This review delineates how this shift in paradigm, given the differences in co-stimulatory and co-inhibitory signal depending on the maturation stage, could profoundly affect our understanding of the CD28/CD80-86/CTLA-4 blockade and highlights the potential advantages of selectively targeting CD28, instead of CD80/86, to control post-transplant immune responses.
authors: Unité Mixte de Recherche, UMR_S 1064, Institut National de la Santé et de la Recherche Médicale , Nantes , France ; Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes , Nantes , France.
authors: Simon
authors: S
authors: Ville
authors: Unité Mixte de Recherche, UMR_S 1064, Institut National de la Santé et de la Recherche Médicale , Nantes , France ; Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes , Nantes , France ; Effimune SAS , Nantes , France.
authors: Nicolas
authors: N
authors: Poirier
authors: Unité Mixte de Recherche, UMR_S 1064, Institut National de la Santé et de la Recherche Médicale , Nantes , France ; Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes , Nantes , France.
authors: Gilles
authors: G
authors: Blancho
authors: Unité Mixte de Recherche, UMR_S 1064, Institut National de la Santé et de la Recherche Médicale , Nantes , France ; Institut de Transplantation Urologie Néphrologie (ITUN), Université de Nantes , Nantes , France ; Effimune SAS , Nantes , France.
authors: Bernard
authors: B
authors: Vanhove
keywords: CD28; CTLA-4; CTLA4-Ig; costimulation blockade; effector T cell; heterologous immunity; memory T cell; transplantation immunology