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The Promiscuous T-cell

Posted on 8. September, 2011.

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T-cells are a vital type of white blood cell that scan for cellular abnormalities and infections. They recognise disease-associated antigens via a surface receptor called the T-cell antigen receptor (TCR). If there were a specific TCR for every single antigen, no mammal could possibly contain all the T-cells it needs. This suggests that T-cell recognition must be highly degenerate. Yet highly promiscuous TCRs would appear to be equally impossible: they are bound to recognise self as well as non-self antigens.  In the next issue of Science Progress, mathematical analysis helps to resolve the paradox of the promiscuous TCR.

Specific T-cell activation in an unspecific T-cell repertoire

HUGO A. VAN DEN BERG, CARMEN MOLINA-PARÍS and ANDREW K. SEWELL

ABSTRACT

T-cells are a vital type of white blood cell that circulate around our bodies, scanning for cellular abnormalities and infections. They recognise disease-associated antigens via a surface receptor called the T-cell antigen receptor (TCR). If there were a specific TCR for every single antigen, no mammal could possibly contain all the T-cells it needs. This is clearly absurd and suggests that T-cell recognition must, to the contrary, be highly degenerate. Yet highly promiscuous TCRs would appear to be equally impossible: they are bound to recognise self as well as non-self antigens.  We review how contributions from mathematical analysis have helped to resolve the paradox of the promiscuous TCR. Combined experimental and theoretical work shows that TCR degeneracy is essentially dynamical in nature, and that the T-cell can differentially adjust its functional sensitivity to the salient epitope, “tuning up” sensitivity to the antigen associated with disease and “tuning down” sensitivity to antigens associated with healthy conditions. This paradigm of continual modulation affords the TCR repertoire, despite its limited numerical diversity, the flexibility to respond to almost any antigenic challenge while avoiding autoimmunity.

Mathematical immunology as a discipline is only justified if mathematicians can provide immunologists with a theoretical support that affords deeper insights, rigorous quantification, as well as experimentally testable hypotheses. We have tried to argue the case by exhibiting various instances where such modelling leads to new immunological ideas or experiments. Working together as mathematical modellers and as experimentalists, we have shown that TCR recognition is a graded phenomenon, expressible as functional sensitivity (pEC50 ).  A clone’s degeneracy is exactly characterised by its functional sensitivity distribution. The fact that T-cells can modulate this degeneracy using costimulatory receptors and TCR-coreceptors suggests numerous interesting new experiments as well as immune system-based therapies. The analysis indicates that T-cells are capable of differential regulation of functional sensitivity – the key to the paradox of TCR promiscuity.

Doi:10.3184/003685011X13139280383942

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