Some of you might be interested in a new paper which we have just published in Frontiers in Immunology (link). The paper outlines a new model built on cellular cooperation to explain the establishment of peripheral T cell tolerance. Unusually, the paper is wholly theoretical. The paper is also somewhat technical, since the model is formulated mathematically as a linear programing optimization problem that can be implemented as a multiplicative update algorithm, which shows a rapid convergence to a stable state. We (i.e. the authors) would welcome feedback on the paper, as it represents the first step in a more ambitious plan to build a broader theoretical framework underpinning the human immune system.
The topic I want to discuss here, however, relates to some fundamental predictions of the model, with far reaching implications across many areas of immunology. In brief the model predicts that anti-self T cells remain present as part of the normal self-tolerant T cell repertoire. The recognition that cells with the potential to react against self are present in normal healthy people (i.e. thymic deletion is not complete) is now widely accepted. A particularly striking example is the latest paper from Mark Davis’s lab. http://www.ncbi.nlm.nih.gov/pubmed/25992863 ). The model further predicts, however, that some of these anti-self T cells will become activated (to a greater or lesser extent), whenever an immune response to a foreign antigen (e.g. a pathogen) is initiated. I formulate the possible significance of these predictions as three clear and testable hypotheses :
- T cells carrying receptors which recognise and respond to self are activated whenever there is a response to a foreign antigen.
- The dynamics of anti-self and anti-foreign T cell activation and proliferation will generally be different, such that tolerance to self is usually rapidly re-established.
- The self-responsive T cells play a key role in amplifying and strengthening normal responses to foreign antigen.
If correct, these hypotheses have wide-ranging implications for many aspects of immunity. I select just three settings in which anti-self responses may play a key role in immune protection or immune pathogenesis:
- Cancer. The extraordinary successes of anti-checkpoint inhibitors in many types of cancer suggest a paradox for conventional theories of specific antigen-driven immunity. There is increasing evidence that the efficacy of checkpoint inhibitor therapy is driven by responses to non-self “neoantigens” (for example see a recent paper from the Schumacher http://www.ncbi.nlm.nih.gov/pubmed/25531942) . Yet specific responses against such neoantigens, in the context of a mutationally unstable tumour, might be expected to rapidly drive the emergence of escape mutations, and the outgrowth of resistant tumour clones. The profound and long lasting responses observed clinically may depend on a concomitant but transient activation of polyclonal “helper” antiself responses, bolstered by the therapeutic suppression of natural self-regulating networks.
- Tuberculosis. There is a growing appreciation that “successful” immunological control of Mycobacterium tuberculosis infection reflects a subtle balance between too strong and too weak an immune response. Indeed the “caseating granuloma” which epitomises tuberculosis is a classic example of damage to self resulting from responses to foreign antigens. The hypotheses outlined above suggest that the robust and chronic stimulation of anti-mycobacterial responses may drive a concerted antiself response which will overcome the normal homeostatic regulatory mechanisms and result in autoimmunity and cell death.
- HIV. Despite decades of research, the exact mechanism which drives AIDS pathogenesis remain unclear. In particular, the rapid turnover of T cells far exceeds the predicted number of infected T cells, and suggests an important role for large scale “bystander” killing of uninfected T cells. As in the case of tuberculosis, the persistent strong immune response to HIV antigens may activate a sustained and pathogenic antiself response, which will contribute to the gradual erosion of the T cell compartment.
The hypotheses and these illustrative examples of how they may operate were stimulated by a purely theoretical paper, a relative rarity in the immunological literature. Theoretical physics has a well-established and respected role within the physics corpus. In contrast, theoretical biology (including theoretical immunology) remains very much a poor relation (the Journal of Theoretical Biology’s most recent impact factor was a modest 2.1). It is true that in the absence of experimental data, the hypotheses presented remain speculative. Nevertheless, I hope that putting these ideas in the public domain may stimulate experiments which will support, or perhaps falsify the hypotheses. It is time our concepts of self-nonself balance were revisited.