Recently discovered T cell subsets cannot keep their commitments.

After activation by antigen/MHC (signal 1) and CD28-dependent co-stimulation (signal 2), resting CD4(+) T cells commit to one of a variety of functionally and molecularly defined phenotypes. Two long established CD4 phenotypes, Th1 and Th2 cells, have been regarded as terminally differentiated formats. Recently, two additional phenotypes, tissue-protective regulatory (Tregs) and tissue-destructive Th17 T cells, have also been discovered, and neither represents a terminally differentiated phenotype. Rather, Tregs and Th17(+) cells respond to cues provided by the inflammatory texture in which these cells reside. We review the important scientific and therapeutic implications of these differences herein.