Basic science for the clinician 56: inducible T-cell costimulator--the world of costimulation gets more...

They say that nothing is assured in this world but change. And this applies in a cynical way to immunology: nothing is assured--we can never rest with an assumption that we know it all because there are always more apparent complications when analyzing immune mechanisms (someday, perhaps we will arrive on a "grand scheme" that elegantly explains it all, just as our brethren in particle physics seek the Higgs boson and the completion of a better model--I am not holding my breath awaiting completion of our task!). In a recent article in this series, we explored CTLA4 as a counterregulator of the CD28-CD80/86 costimulatory pathway. However, treatment with CTLA4 does not entirely shutdown the immune system; engineering animals so that the CD28-CD80/86 pathway no longer functions does not prevent functional protective immune responses. Thus, there must be yet another pathway. And there is--an "inducible T-cell costimulator" (ICOS) is found on T cells (activated, not naive), which has a single ligand on antigen-presenting cells (ICOS ligand, B7-RP-1). The rapid induction of ICOS speaks to its importance in T-cell function; however, ICOS is more relevant to the stimulation of effector and memory T cells than is CD28 signaling. There are similarities and differences, interactions, and overlaps between the 2 pathways, some of which are very useful in understanding the immunopathogenesis of immune diseases.