The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences

Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system.