Signals for anergy and apoptosis

What is the nature of the negative signals for tolerance? Initial stimulation of both T and B cells involve receptor coupling via Src family protein tyrosine kinases (PTKs), e.g. to phospholipase C and the production of inositol phospholipids, some of which lead to calcium mobilization, and other products cause activation of protein kinase C and subsequent phosphorylation of critical substrates leading to gene transcription. Other downstream substrates involve MAP kinase activation and both common and alternative transcriptional events. Studies in T cell clones suggest that if the initial calcium signal is given alone or abortively, then the T cell is rendered anergic. Whether this process can be mimicked in B cells remains to be determined although the idea that abortive stimulation of B cells in the absence of costimulation via T cell help is not only appealing, but consistent with several models. One paradigm that has developed is that there is great commonality between negative signals for tolerance (growth arrest, anergy, apoptosis) and the initial positive signals in lymphocyte stimulation. The two-signal hypothesis indeed proposes that it is the second signal that is the determining factor.

Therefore, what is the nature of positive costimulation? As summarized in Figure 1, T cells recognize costimulatory molecules of the B-7 family via the CD28 and CTLA-4 receptors. Blocking these interactions can modulate a stimulatory response towards tolerance; indeed, clinical trials in this direction are in progress. For B cells, the CD40 receptor can positively signal for their growth and differentiation via T cell CD40L and can overcome tolerogenic (signal 1) stimuli. The precise nature of the biochemical signals is unclear, but is likely to involve kinase activation and a balance of interacting transcription factors. Understanding this balance will provide new approaches for clinical tolerance induction.

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