Degrees of Tolerance

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Science  03 Aug 2007:
Vol. 317, Issue 5838, pp. 572
DOI: 10.1126/science.317.5838.572b

The affinity of a T cell receptor for its ligand [a peptide bound by a molecule of the major histocompatibility complex (pMHC)] dictates whether a T lymphocyte will become active. However, activation also depends critically on a series of parallel signals, and when these are lacking, the effect of any pMHC complex is a state of anergy (or permanent inactivation) of the T cell. This is an important means by which immune tolerance to self-constituents of the body is maintained.

Using intravital imaging, Skokos et al. observed that as T cells engaged pMHC complexes of differing affinities for the T cell receptor in lymph nodes in the absence of coactivating signals, their behavior varied considerably. Thus, although under these conditions pMHCs of all affinities induced anergy and led to the retention of circulating T cells in the lymph nodes, only those with a high affinity triggered the flux of Ca2+ that signals the T cells to slow down. Medium-affinity complexes, on the other hand, failed to stimulate Ca2+ flux, but did induce a low level of division and cytokine production. Finally, the low-affinity ligands did not evoke any biochemical event or change in cellular motility but instead rapidly induced an inactive state. Thus, a hierarchy of anergic states may exist for T cells, depending on differences in the binding strength of antigens they meet under steady-state conditions. — SJS

Nat. Immunol. 8, 835 (2007).

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