

The immune system has traditionally been conceived as a system of recognition and elimination of foreign living entities, seen as potential pathogens, and hence threats for the integrity of the organism. Yet we have seen that, in virtually all species, many bacteria are actively tolerated by the immune system, and even participate in host defense against pathogens and in the development of the immune system itself (Mazmanian et al.2005; Round and Mazmanian 2009).

The immune system cannot be understood anymore as a system of rejection; it is instead, in all organisms, a system of selective but constant integration of some living entities (Pradeu 2012). A key challenge for current immunology, therefore, is to determine the mechanisms through which mutualistic microorganisms are tolerated, while pathogenic ones are rejected (Chu and Mazmanian 2013).

Philosophers of biology may play an important role in this discussion, as answers will depend on the adopted theoretical framework. Can the self-nonself theorybe accommodated to integrate recentdata on the massive presence of symbionts in the host? Or will the danger theory, suggested by Polly Matzinger (2002) and stating that the immune system does not respond to “nonself” but to “danger” signals, constitute a convincing alternative?

In collaboration with immunologists, Thomas Pradeu has suggested a different theoretical framework, the “discontinuity theory”, which proposes that immune responses are triggered byrapid molecular changes in the organism (be they of internal or external origin) (Pradeu and Carosella 2006a; Pradeu, Jaeger and Vivier 2013). It is not clear, however, how this framework can account for the tolerance of symbiotic bacteria in the newborn, given that the newborn is in fact massively and rapidly colonized at birth, which suggests that its immune system should respond to this rapid phenotypic change.

A fundamental objective of IDEM is, therefore, to characterize both theoretically and experimentally the criteria for the triggering of an effector immune response, and the reasons that explain why the microbiota, far from being rejected by the organism, is actively tolerated. The question of how to account for tolerance to the microbiota will be part of a larger inquiry about the interactions between immunology and developmental biology.

These two fields have too long been considered as having little to say one to the other. But, as Jules Hoffmann showed in his 2011 Nobel Lecture, development and immunity are strongly intertwined, as exemplified by the role of drosophila Toll receptors, or by the action of macrophages and the complement in vertebrates.

It is likely that the immune system plays a crucial role in development in all species, as this system can exert a destructive function, for instance through apoptosis (induced cell death), of organic constituents that have become too numerous or superfluous. Indeed, to build an organism often implies to destroy some of its tissues, and it appears that the immune system fulfills this task (Jacobson et al.1997).

Theories currently available in immunology have difficulties in explaining some crucial phenomena studied by developmental biology, from the tolerance of numeroussymbiotic bacteria to the very possibility of massive phenotypic changes in the host, such as metamorphosis (a frequent phenomenon in nature), sexual maturation, regeneration, etc.

Recent data also suggest that at least some cancers appear through developmental-like mechanisms, as if cancerogenesis was an abnormal “reactivation” of processes usually involved in development (in particular angiogenesis: Tammela et al. 2008); an important question is to understand how the immune system interacts with these developing cancerous tumors.

Overall, it is crucial for IDEM to characterize in detail the interface between immunology and developmental biology, and in particular to assess the discontinuity theory in face of data on the way the organism, throughout its life, can sometimes change very rapidly.

Thus, the major questions raised by this sub-project are:

  • What role does the immune system play in the integration and the tolerance of mutualistic microbes?
  • Which is the most appropriate theoretical framework in immunology to account for the tolerance of mutualistic microbes?
  • How doesthe immune system cope with rapid phenotypic changes in the organism?
  • What role does the immune system play in the maintenance of biological identity through time?



Chu, H., and Mazmanian, S. K. (2013). Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nature Immunology14(7), 668-675

Jacobson, M. al. (1997). Programmed cell death in animal development. Cell88, 347-354

Matzinger, P. (2002). The Danger Model: A Renewed Sense of Self. Science296, 301-305

Mazmanian, S. al. (2005). An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell122(1), 107-118

Round, J. L., andMazmanian, S. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology9(5), 313-323

Pradeu, T. (2012). The Limits of the Self: Immunology and Biological Identity. New York,Oxford University Press

Pradeu, T., and Carosella, E.D. (2006a). On the definition of a criterion of immunogenicity. Proceedings of the National Academy of the Sciences USA, 103(47), 17858-61

Pradeu, T., Jaeger, S., and Vivier, E. (2013). The Speed of Change: Towards a Discontinuity Theory of Immunity? Nature Reviews Immunology13, 764-769

Tammela, T. et al. (2008). Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature454,656–660