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João Sousa

A Mathematical Model of TCR Signalling

J. Sousa§,# & J. Carneiro§


§Instituto Gulbenkian de Ciência, Apartado 14, 2781 Oeiras Codex
#Grupo de Bioquímica e Biologia Teóricas, Instituto Bento da Rocha Cabral
http://www.igc.gulbenkian.pt/eao/ti/

T cells are an important part of the regulation of the immune response. Central to T cell function is the activation of the T cell antigen receptor (TCR) by its specific ligand, the MHC-peptide expressed at the surface of an antigen-presenting cell (APC). The TCR signalling pathways, which are involved in the activation of T cells, have received much attention from experimental studies (reviewed in [1]). Many components have been identified and characterised, but the stoichiometry of TCR engagement and the molecular mechanism responsible for the initiation of signalling by the TCR is still controversial [2, 3].

We have employed mathematical modelling techniques to analyse experimental data on the kinetics of TCR down-regulation [2] to identify key kinetic properties of TCR engagement and triggering and contribute to resolve some of the controversy.

Based on this analysis, we propose a model of TCR triggering and down-regulation (fig. 1), which is able to explain the available experimental data on TCR down-regulation [4], and predicts:

  1. That TCR triggering is a highly co-operative event with ultra-sensitivity to ligand presentation. We are continuing to pursue the mechanistic implications of the high cooperativity of TCR triggering.

  2. The existence of peaks of triggered TCRs on the surface of the T cell. These peaks last up to 50 min after the T cell is engaged by the APC and provide a time-window for the activation of downstream cascade of TCR signalling.

  3. That TCR triggering and down-regulation causes tuneable thresholds for T cell activation [5,6]. The conjugation of T cells by APCs loaded with ligand can regulate the levels of TCR expression and condition the efficiency of successful stimulation of lymphocytes.

This model also provides a framework for further study of down-stream signalling events.

  1. Germain, R.N. & Stefanova I. (1999) Annu Rev Immunol. 17: 467-522.
  2. Valitutti, S., et al. (1995) Nature. 375: 148-51.
  3. Bachmann, M.F., et al. (1998) Eur J Immunol. 28: 2571-9.
  4. Sousa J. & Carneiro J. (2000) Eur J Immunol. 30: 3219-27.
  5. Grossman Z., Paul W.E. (1992) Proc Natl Acad Sci U S A. 89: 10365-9.
  6. Viola A., Lanzavecchia A. (1996) Science. 273: 104-6.

 

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