Role of microbiota in evolution of adaptive immune system

Source: Science 24 December 2010: 
Vol. 330 no. 6012 pp. 1768-1773 
DOI: 10.1126/science.1195568

Has the Microbiota Played a Critical Role in the Evolution of the Adaptive Immune System?

1. Yun Kyung Lee and Sarkis K. Mazmanian^*
   

   
    

• Microbes reside in several anatomical sites of human body including the skin, vagina, and mouth.
  
• Lower gastrointestinal tract of mammals harbor the greatest density and diversity of commensal microorganisms (including bacteria, archaea, fungi, viruses, protozoans, and helminthes.
  
• It has been observed that the development of gut associated lymphoid tissue (GALT), the first line of defense for the intestinal mucosa, is defective in germ free animals.
  
• It has also been observed that germ free mice display fewer and smaller Peyer's patches, smaller and less cellular mesenteric lymph nodes and less cellular lamina propia of small intestine relative to animals with a microbiota. Furthermore, these mice have been shown to exhibit reduced expression of TLRs and MHC class II molecules.
  
• Number of CD4+ T cells is also reduced in lamina propria of germ free mice. Development of isolated lymphoid follicles is also defective in the absence of microbes.
  
• Multiple proportions of intestinal immune cells require the microbiota for their development and function.
  
• In addition to its effect on intestinal immunity microbiota also effects extra intestinal immunity.
  
• It has also been observed that germ free mice are more susceptible to microorganisms like Shigella, Bacillus and Leishmania. Thus, in addition to development microbiota also effects functional aspects of intestinal and systemic immunity.
  
• Host mechanisms and the microbiota may have evolved to collaborate against infectious agents.
  
• Studies have shown an antagonistic relationship between microbiota and overt pathogens.
  
• Harnessing the immunomodulatory capabilities of microbiota may offer new avenues for development of antimicrobial therapies for infectious diseases.
  
• Microbiota play important roles in effector CD4+ T cell differentiation. During infection microbial and host signals provide cues to naïve CD4+ T cells to differentiate into various proinflammatory and anti-inflammatory subsets.
  
• Microbiota has been shown to affect the TH1-TH2 balance in the systemic immune compartments.
  
• Studies have shown that TH17 cell development in the gut is specifically affected by commensal bacteria.
  
• Of the various microbial species that constitute the microbiota of mice, only segmented filamentous bacteria (SFB) have been shown to direct intestinal T helper cell development.
  
• Researchers from around the world have proposed that life style changes have caused a fundamental alteration in the association of humans with the microbial world. The alteration in composition of healthy microbiota leading to altered microbial colonization is known as dysbiosis.
  
• Although it is not known yet whether dysbiosis causes any human diseases, it may affect autoimmunity by altering the balance between toleragenic and inflammatory members of the microbiota.
  
• 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), leading to a balance of Treg and TH17 cell activities.
  
• Altered community composition of the microbiome due to life-style, known as dysbiosis, may represent this disease-modifying component. An increase in proinflammatory microbes (for example, SFBs in animalmodels)may promote TH17 cell activity to increase and thus predispose genetically susceptible people to TH17-mediated autoimmunity.
  
• The imbalance between TH17 cells and Tregs ultimately leads to autoimmunity.
  
• We propose that certain microbes, such as SFBs, that can peacefully coexist with a healthy host but still retain pathogenic potential be termed "pathobionts" to distinguish them from opportunistic pathogens that are acquired from the environment and cause acute infections.
  
• The adaptive immune system distinguishes between self and foreign antigens and mounts an appropriate response to clear invading pathogens by recognizing non-self molecules.
  
• The adaptive immune system must either tolerate or ignore the microbiota.
  
• Several studies suggest that symbiotic bacteria have evolved the mechanisms to suppress unwanted inflammation toward the microbiota by actively inducing mucosal tolerance.
  
• The authors propose a model for co-evolution of adaptive immune system with the microbiota.
  
• According to this model, The adaptive immune system develops under the control of the vertebrate genome to produce various cell types. The evolutionarily ancient molecule TGFb directs the differentiation of Foxp3+ Treg cells.
  
• Over millennia of coevolution, commensal microbes (B. fragilis used as an example here) produced molecules that networked with the primordial immune systemto help expand various Treg cell subsets (for example, IL-10–producing Foxp3+ Treg cells).
  
• Pro-inflammatory pathobionts (such as SFBs) may have induced TH17 cell differentiation to increase mucosal defenses against enteric pathogens.
  
• The modern adaptive immune system may have arisen from two distinct events: Tregs and Th17 cell types evolved independently or through the sequential development of TH17 cells from Treg cell precursors.
  
• Taken together, the modulation of Tregs and TH17 cells by commensal microorganisms and pathobionts, respectively, appears to shape the immune status of the host and thus represents a possible risk factor for autoimmune diseases that appears to depend on balanced Treg-Th17 proportions.