Research Article: Redefining the Immune System as a Social Interface for Cooperative Processes

Date Published: March 21, 2013

Publisher: Public Library of Science

Author(s): Eric Muraille, Glenn F. Rall.


Partial Text

Viewed from a neo-Darwinian perspective, the main function of the metazoan immune system (IS) is to insure host integrity against invading microorganisms, which are only considered as selfish competitors that reduce the host’s resources, inflict tissue damage, and ultimately compromise host fitness. Coevolution of the host and these competitors has been described as a perpetual arms race (known as the Red Queen hypothesis, Van Valen, [1]). This vision implicitly suggests that “The IS evolved under selective pressure imposed by infectious microorganisms” (Janeway, [2]) and that the ultimate objective of the IS is to conserve the integrity and sterility of the host (Figure 1A). In fact, numerous observations from microbiology and ecology have challenged this paradigm and suggest that infectious organisms and the IS play a crucial, unexpected role in evolution:

Simple observations of ecosystems lead us to conclude that mutually beneficial interactions (cooperative behavior) are prevalent throughout the biological world, both within and across species and at all levels from genes to societies. As suggested by Maynard Smith [32], cooperative interactions seem to be the key to understanding the major transition in life. However, their selection and relevance have challenged theorists for decades, in part because of the “Prisoner’s Dilemma” [33], which has dominated the literature on cooperation. This paradigm depicts how two unrelated players benefit from mutual cooperation, and how a cheating player can increase its advantage by reaping the benefits of the cooperating population without contributing to public goods (PGs). Eventually, the entire population may collapse when the proportion of cheaters increases beyond a critical point, a scenario known as “the tragedy of the commons,” which was initially described by Hardin [34]. Explaining how selection can promote and stabilize a trait that benefits another individual constitutes one of the greatest challenges in evolutionary biology.

There many costs and consequences of acquisition of SIs for all organisms. Obvious costs of the SI are those for energy and collateral damage due to policing mechanisms that neutralize cheaters such as the inflammatory immune response [46]. However, another important cost is the risk of autoimmunity. Autoimmunity, classically defined in mammalian IS, is the failure of the IS to recognize what is self and what is foreign, resulting in an immune response against self. I propose that autoimmunity is a risk associated with all SIs and thus shared by all consortia. In keeping with this argument, potential sources of the autoimmune reaction have been reported in bacteria and linked to the CRISPR system [47] and in social amoebae [48].

In conclusion, I propose that the innate and adaptive metazoan IS has evolved under selective pressure favoring symbiosis, a source of genetic diversity, HGT, and cooperation that globally promote better adaptation to selective pressure. In this view (Figure 2), the metazoan IS appears, like all SIs, to be responsible for: (i) management of the cooperation of syngeneic cells, which may explain the numerous functions of the IS in the development and maintenance of organisms in the absence of infection; (ii) detection of selfish/cheater behavior of syngeneic or allogeneic cells; and (iii) elimination and memorization of cheaters. This invites reinterpretation of the condition for IS activation. The “danger signal” proposed by Matzinger [50] and POPs [42] could be redefined as “selfish/cheater signals.” The importance of selfish/cheater behavior in activation of the IS is demonstrated by the ability of the IS to tolerate our allogeneic cooperative microbiota and fight syngeneic selfish cells (tumors).




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