Has the microbiota played a critical role in the evolution of the adaptive immune system? - PubMed (original) (raw)

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Has the microbiota played a critical role in the evolution of the adaptive immune system?

Yun Kyung Lee et al. Science. 2010.

Abstract

Although microbes have been classically viewed as pathogens, it is now well established that the majority of host-bacterial interactions are symbiotic. During development and into adulthood, gut bacteria shape the tissues, cells, and molecular profile of our gastrointestinal immune system. This partnership, forged over many millennia of coevolution, is based on a molecular exchange involving bacterial signals that are recognized by host receptors to mediate beneficial outcomes for both microbes and humans. We explore how specific aspects of the adaptive immune system are influenced by intestinal commensal bacteria. Understanding the molecular mechanisms that mediate symbiosis between commensal bacteria and humans may redefine how we view the evolution of adaptive immunity and consequently how we approach the treatment of numerous immunologic disorders.

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Figures

Fig. 1

Fig. 1

The microbiome of various anatomical location of the human body. Numerous bacterial species colonize the mouth, upper airways, skin, vagina and intestinal tract of humans. The phylogenic trees show the speciation of bacterial clades from common ancestors at each anatomical site. Although the communities in different regions of the body share similarities, they each have a unique site-specific ‘fingerprint’ made of many distinct microbes. Each site has a very high level of diversity, as shown by the individual lines on the dendograms. Data is from the NIH funded Human Microbiome Project, and circles represent bacterial species whose sequences are known. NOTE TO SCIENCE EDITORS: the figure of the body was taken from GOOGLE images and the phylogenic trees were taken from the Human Microbiome Project. Please address any copyright issues and/or redraw figures.

Fig. 2

Fig. 2

How the microbiome and the human genome contribute to inflammatory disease. In a simplified model, the community composition of the human microbiome helps to shape the balance between immuneregulatory (Treg) and pro-inflammatory (Th17) T cells. The molecules produced by a given microbiome network work with the molecules produced by the human genome to determine this equilibrium. (A) In a healthy microbiome, there is an optimal proportion of both pro- and anti-inflammatory organisms (represented here by SFBs and B. fragilis), which provide signals to the developing immune system (controlled by the host genome) that leads to a balance of Treg and Th17 cell activities. In this scenario, the host genome can contain ‘autoimmune specific’ mutations (represented by the stars), but disease does not develop. (B, C) The genome of patients with multiple sclerosis, type I diabetes, rheumatoid arthritis and Crohn’s disease contain a spectrum of variants that are linked to disease by genome wide association studies (reviewed in (61)). Environmental influences, however, are risk factors in all of these diseases. Altered community composition of the microbiome due to lifestyle, known as dysbiosis, may represent this disease modifying component. An increase in pro-inflammatory microbes, for example SFBs in animal models, may promote Th17 cell activity to increase and thus predispose genetically susceptible people to Th17-mediated autoimmunity (B). Alternatively, a decrease or absence in anti-inflammatory microbes, for example B. fragilis in animal models, may lead to an under-development of Treg cell subsets (C). The imbalance between Th17 cells and Tregs ultimately leads to autoimmunity.

Fig. 3

Fig. 3

A model for the co-evolution of adaptive immunity with the microbiota. (A) The adaptive immune system develops under the control of the vertebrate genome to produce various cell types. The evolutionarily ancient molecule TGFβ directs the differentiation of Foxp3+ Treg cells. Although the earliest mammals contained a gut microbiota, bacteria may or may not have influenced features of the primordial adaptive immune system. (B) Over millennia of co-evolution, commensal microbes (B. fragilis used as an example here) produced molecules that networked with the primordial immune system to help expand various Treg cell subsets, for example IL-10-producing Foxp3+ Treg cells. This process may have evolved to allow these microorganisms to colonize the gut by inducing antigen-specific tolerance to the microbiota. (C) Pro-inflammatory pathobionts (such as SFBs) may have induced Th17 cell differentiation to increase mucosal defenses against enteric pathogens. (D) The modern adaptive immune system may have arisen from 2 distinct events: Tregs and Th17 cell types evolved independently (A to B and A to C), or through the sequential development of Th17 cells from Treg cell precursors (A to B to C to D). This may have been achieved by a combinatorial signal of TGFβ, augmented by the addition of IL-6 to promote Th17 cell evolution over time (inset). Together, the modulation of Tregs and Th17 cells by commensal and pathobionts, respectively, appears to shape the immune status of the host, and thus represents a possible risk factor for autoimmune diseases which appear to depend on balanced Treg/Th17 proportions.

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