The Role of Costimulatory Molecules in Directing the Functional Differentiation of Alloreactive T Helper Cells

Costimulatory molecules are a heterogenous group of cell surface molecules that act to amplify or counteract the initial activating signals provided to T cells from the T cell receptor following its interaction with an antigen/major histocompatibility complex, thereby influencing T cell differentiation and fate. Although costimulation was previously thought to be indispensable for T cell activation at all stages of development, it is now known that the requirements for costimulation, and the costimulatory molecules involved, vary according to the stage of T cell differentiation. The ability to influence T cell fate is of paramount interest in the field of transplantation as we seek therapeutic options that inhibit detrimental alloimmune responses whilst simultaneously promoting allograft tolerance. As with many immune mechanisms, there is a degree of functional overlap between certain costimulatory molecules, whereas some have diametrically opposite effects on different T cell subsets despite sharing common ligands. This is a critical point when considering these molecules as therapeutic targets in transplantation, as blockade of a costimulatory pathway, although desirable in itself, may prevent the ligation of an essential regulatory coinhibitory molecule. This review discusses the T helper cell lineages pertinent to transplantation and the costimulatory molecules involved in their differentiation. This review discusses the influence of co‐stimulatory molecules on T helper cell differentiation in the alloimmune response, with particular emphasis on the therapeutic implications of co‐stimulatory blockade.