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

Co-stimulatory 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 (TCR) following its interaction with an antigen/major histocompatibility complex (MHC), thereby influencing T cell differentiation and fate. While co-stimulation was previously thought to be indispensable for T cell activation at all stages of development, it is now known that the requirements for co-stimulation, and co-stimulatory 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 co-stimulatory molecules, while 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 co-stimulatory pathway, while desirable in itself, may prevent the ligation of an essential regulatory co-inhibitory molecule. This review discusses the T helper cell lineages pertinent to transplantation and the co-stimulatory molecules involved in their differentiation.