Adaptive immunity refers to the body’s ability to mount specific responses against biotic threats such as pathogenic organisms and cancerous cells. Each response leaves a memory trace that allows a more rapid response when a similar threat reappears later on in life. This recall response can be so swift that exposure to the pathogen often seems to pass without discernible symptoms, whence immūnitas “freedom from.”
Specific recognition underlies adaptive immunity and is conferred by receptors located on the outer surface of a special class of lymphocytes called T cells. A repertoire of millions of different molecules, each with its own molecular specificity, is generated by means of non-germ line genetic recombination. Large as this repertoire may be, it is still dwarfed by the universe of molecular identities against which the system might be called upon to mount a response. Adequate coverage of this vast universe by a comparatively modest T-cell receptor (TCR) repertoire is attained via the degeneracy of molecular recognition; each TCR can respond to a range of different molecules.
Immune tolerance is the freedom from T-cell attack on healthy tissues. If each TCR were highly specific, such attacks might be averted by elimination of self-reactive TCRs. However, TCR recognition is highly degenerate, every TCR being capable of productive interaction with several self-antigens: elimination of all self-reactivity is out of the question. Moreover, self-recognition is a fundamental prerequisite for the maintenance of diversity in the TCR repertoire.
The reconciliation of degeneracy and tolerance is the fundamental problem of adaptive immunity. Attacking the available data using an approach that combines the strengths of mathematical modelling and bioinformatics, we have obtained evidence that the immune system accomplishes this delicate balancing act by a continual, dynamic process of adjustment that takes place in each individual T cell, a process that is guided by clues emanating among others from the professional antigen-presentation system. In particular, modification and rearrangement of accessory molecules such as the co-receptors CD8 and CD4 underpin a “ligand focussing’’ mechanism whereby a strong response is evoked by only a small, actively selected portion of a TCR’s spectrum of potential agonists.