Complexities of CD28/B7: CTLA-4 Costimulatory Pathways in Autoimmunity and Transplantation

Abstract

Recent advances in the understanding of T cell activation have led to new therapeutic approaches in the treatment of immunological disorders. One attractive target of intervention has been the blockade of T cell costimulatory pathways, which result in more selective effects on only those T cells that have encountered specific antigen. In fact, in some instances, costimulatory pathway antagonists can induce antigen-specific tolerance that prevents the progression of autoimmune diseases and organ graft rejection. In this review, we summarize the current understanding of these complex costimulatory pathways including the individual roles of the CD28, CTLA-4, B7-1 (CD80), and B7-2 (CD86) molecules. We present evidence that suggests that multiple mechanisms contribute to CD28/B7-mediated T cell costimulation in disease settings that include expansion of activated pathogenic T cells, differentiation of Th1/Th2 cells, and the migration of T cells into target tissues. Additionally, the negative regulatory role of CTLA-4 in autoimmune diseases and graft rejection supports a dynamic but complex process of immune regulation that is prominent in the control of self-reactivity. This is most apparent in regulation of the CD4(+)CD25(+)CTLA-4(+) immunoregulatory T cells that control multiple autoimmune diseases. The implications of these complexities and the potential for use of these therapies in clinical immune intervention are discussed.

CTLA4 Silencing with siRNA Promotes Deviation of Th1/Th2 in Chronic Hepatitis B Patients

“…The CTLA4 ligands have an inhibitory role on T cell activation and may contribute to peripheral tolerance (1). Upon B7-1 or B7-2 engagement, CTLA4 expressed on the surface of activated T lymphocytes signals for cell-cycle arrest and attenuating the function of effectors (2,3). Previous studies have demonstrated that blockage of signaling transduction between CD28 and CTLA4-Ig inhibited the response of T cells and prolonged the allograft survival in several rodent and organ transplantation models (4)(5)(6)(7).…”

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

“…CTLA-4 is a major costimulatory receptor that negatively regulates T cell activation [1][2][3][4]. CTLA-4 has a homologous structure to CD28 and binds to the same ligands, CD80/CD86, as CD28, but with much higher affinity.…”

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

“…These molecules may provide critical positive signals that augment and sustain T cell responses, or negative signals to attenuate or terminate immune responses [2][3][4][5][6].…”