T-cell anergy and peripheral T-cell tolerance

The discovery that T-cell recognition of antigen can have distinct outcomes has advanced understanding of peripheral T-cell tolerance, and opened up n ew possibilities in immunotherapy. Anergy is one such outcome, and results from partial T-cell activation. This can arise either due to subtle alterat ion of the antigen, leading to a lower-affinity cognate interaction, or due to a lack of adequate co-stimulation. The signalling defects in anergic T cells are partially defined, and suggest that T-cell receptor (TCR) proxima l, as well as downstream defects negatively regulate the anergic T cell's a bility to be activated. Most importantly, the use of TCR-transgenic mice wa s provided compelling evidence that anergy is an in vivo phenomenon, and no t merely an in vitro artefact. The:je findings raise the question as to whe ther anergic T cells have any biological function. Studies in rodents and i n man suggest that anergic T cells acquire regulatory properties; the regul atory effects of anergic T cells require cell to cell contact, and appear t o be mediated by inhibition of antigen-presenting cell immunogenicity. Clos e similarities exist between anergic T cells, and the recently defined CD4( +)CD25(+) population of spontaneously arising regulatory cells that serve t o inhibit autoimmunity in mice. Taken together, these findings suggest that a spec- tl um of regulatory T cells exists. At one end of the spectrum are cells, such as anergic and CD4(+)CD25(+) T cells, which regulate via cell- to-cell contact. At the other end of the spectrum are cells which secrete a ntiinflammatory cytokines such as interleukin 10 and transforming growth fa ctor-beta. Tile challenge is to devise strategies that reliably induce T-ce ll anergy in vivo, as a means of inhibiting immunity to allo- and autoantig ens.