Anergic agonistic and antagonistic signal transduction

T cells activated by the TCR in the absence of costimulation signals lose the capacity to secrete interleukin 2, a state called clonal anergy. Anergy induction appears to involve the calcium/calcineurin pathway as it is blocked by cyclosporine and can be partially mimicked by the calcium ionophore lono-mycin. Analysis of CD3- and CI)28-induced signal transduction has revealed that p21r"-~ remained unac-

tivated and found reduced ERK and JNK enzyme activities in murine anergic T cells. Thus a block in Ras activation may lead to defective transactivation of AP-1 sites in anergic cells and may enable T cells to shut down IL-2 production selectively during anergy.

Initial predictions were that the TCR would function as a simple 'on-off switch for the T cell. Recent studies have indicated that T cell activation is not an all-or-none event, but rather involves a spectrum of biochemical events depending on the precise structure of the peptide-MHC ligand. Altered peptide ligands are analogs of immunogenic peptides in which the TCR contact sites have been substituted. These analogs may have agonistic, partial agonistic or antagonistic effects on T cells. Altered patterns of tyrosine substrate phosphorylation and selective activation of the calcium-signaling pathway are induced by altered peptide ligands. The mechanistic basis for altered ligand signaling remains unknown. The simplest notion to resolve the marked differences in cellular outcome between antigen ligands of differing affinity is to propose a time lag for the full assembly of the TCR signaling complex. Thus, the dissociation rate of the ligand from the TCR most likely determines whether antigen recognition will result in partial or full cellular activation. McKeithan has proposed a kinetic model of TCR signaling in which the complexity inherent in the TCR pathways serves to permit TCRs to finely discriminate between ligands. Some partial peptide agonists induce a state of T cell anergy while others induce altered patterns of cytokine secretion and fail to induce T cell proliferation. It is likely that signal transduction induced by altered peptide ligands has substantial physiologic importance as the pool of altered ligands in vivo is likely very large compared with the number of specific ligands that have selected the T cell repertoire.

See also: Anergy, B cell; CD2; CD4; CD5; CD8; CD28; CD40 and its ligand; C045 (the leukocyte common antigen); Effector lymphocytes; Immunoglobulin gene superfamily; Integrins; Interleukin 2; Lymphocyte function-associated antigen 3 (LFA-3); Phorbol esters; Proliferation, lymphocyte; Protein kinases; Second signals for lymphocyte activation; Superanti-gens; T cell receptor, aß.

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