Revised: May 12, 2014
Accepted: June 10, 2014
Published online: July 27, 2014
Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen (CTLA)-4/B7 interaction (using CTLA-4Ig) and the CD40/CD40L interaction (using anti-CD40L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis (abatacept) and to prevent rejection of renal transplants (belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells (Teff) and regulatory T cells (Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding of the costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.
Core tip: Costimulation blockade (e.g., CD28/B7 and CD40/CD40L blockade) has been successfully used experimentally to induce tolerance to allo- or auto-antigens. Several studies suggest that effector T cells (Teff) and regulatory T cells (Treg) have different requirements regarding costimulation. While blockade of the CD40L receptor does not affect Treg cells and targets Teff cells, the effect of blocking the CD28/cytotoxic T lymphocyte antigen (CTLA)-4/B7 interaction (with CTLA-4Ig) is more difficult to predict and depends on the type, the strength and the stage of an immune process. Importantly, manipulating these costimulatory signals can therefore shift the Treg/Teff cell balance towards dominant Treg cell activity.