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.

Keywords: CD28; CTLA-4; CTLA4-Ig; costimulation blockade; effector T cell; heterologous immunity; memory T cell; transplantation immunology.

Figure 1

CD28 requirement and CTLA-4 mediated inhibition evolve through T cell run, highlighting consequence of different strategies targeting the CD28/CD80/86/CTLA-4 axis. Upper panel: according to the developmental model, during immune response, T cells differentiate progressively ranging from naive to effector via the memory stage. Throughout this process, like a ball rolling down a hill, they lose their proliferative potential but gain effector and homing competences. We assume that simultaneously their activation threshold, and so CD28 dependency, decreases but that conversely the importance of CTLA-4 intrinsic inhibitory signaling gradually increased. Lower panel: dotted line, control condition; red line, CTLA-4 blockade; green line, CD28 selective blockade; blue line, CD80/86 blockade; broken line represent sufficient level for T-cell activation and mounting an efficient response. For naive T cells, due to the lack of CTLA-4 signaling, selective and non-selective CD28 blockade would be equally efficient in controlling their activation. In the case of terminally differentiated T cells, preserving CTLA-4 mediated signals could be essential, especially in the absence of a CD28 requirement, suggesting a relevant advantage of the CD28 selective blockade compared to CD80/86 antagonist. Memory T cells might represent a middle path in which the intensity of the TCR stimulation, more important in allo-immune context especially with direct presentation, is probably critical.