The human intestinal tract is the home of a diverse array of bacterial colonies, settling in as soon as their host begins life. While these colonies were considered to merely coexist with the host for their own survival, decades of study have shown the interaction between bacteria and host is mutually beneficial.  The bacterial colonies benefit by finding their home in the host, while the host benefits from the bacteria’s ability to keep the intestinal tract healthy, specifically by aiding in the absorption of nutrients, and by preventing disease-causing bacteria from taking root. It is also known that the host immune system in the intestinal tract has the uncanny ability to tolerate specifically the “good” intestinal bacteria, while warding off disease-causing bacteria. 

Yet it still remains unclear as to precisely how the immune system tolerates and maintains the healthy intestinal flora, or more importantly, how this tolerance is lost in inflammatory bowel diseases including colitis and Crohn’s disease. To answer these questions, scientists have suggested that the healthy gut bacteria have the capacity to shape the host immune system, ensuring that the immune system can tolerate the presence of “good” bacteria that make up the gut flora. As to how this happens, scientists have recently published 2 remarkable breakthroughs in the recent issues of Nature (May 9th and 23rd issues). In their studies, they discovered two key immune cell populations that are involved in shaping immune tolerance to gut bacteria: the thymus derived regulatory T cells (Treg) and the retinoic-acid-receptor-related orphan receptor-gamma-t-positive innate lymphoid cells (RORgammat+ ILC).

Thymus-derived Tregs are discovered by Dr. Leszek Ignatowicz (George Regents University, GA) to be a crucial cellular player involved in educating the immune system about the diverse bacterial colonies in the intestinal flora of mice. These Tregs emerge in the thymus, populating most of the intestinal and lymphoid organs. In response to the diversity of gut bacteria, Tregs express a repertoire T cell receptors (TCRs) that recognize the antigens characteristic of individual bacterial colonies in the gut. Upon engagement of these receptors, Tregs suppresses the adaptive immune response, specifically through the release of immune-modulatory cytokines such as interleukin-2. Moreover, Ignatowicz discovered that antibiotic-induced changes in the gut flora are reflected by the TCR repertoire of thymus derived Tregs. The results suggest that Tregs are crucial for suppressing immune reactions against gut bacteria, and ensuring the existence of these commensal bacterial colonies is tolerated by the host immune system.

Further adding to the complexity of this picture is the more recent study by Dr. Gregory F. Sonnenberg at the University of Pennsylvania (PA), showing that gut bacteria can also be recognized and protected by a distinct innate lymphoid cell population (ILC) in the intestinal lining of mice.  These cells can be identified by their expression of a receptor dubbed RORgammat, and are so called the RORgammat+ ILC. Sonnenberg further discovered that these cells behave like antigen presenting cells, and can recognize and present antigens from gut bacteria through the major histocompatibility complex class II (MHCII). But rather than activating CD4+ T lymphocytes (adaptive immune cells) through MHCII engagement (in a manner similar to a typical antigen presenting cell), RORgammat+ ILC works by suppressing CD4+ T lymphocytes through MHCII engagement. Moreover, Sonnenberg found that the selective deletion of MHCII specifically in the RORgammat+ ILC population promoted spontaneous intestinal inflammation, suggesting that MHCII signaling in this population is crucial for keeping the CD4+ lymphocytes in check, ensuring that the immune system tolerates the “good” commensal bacteria. Based on these results, Sonnenberg concluded that the RORgammat+ ILC is a new immune cell population that can selectively suppress the adaptive immune response against gut bacteria, ensuring the proper immune tolerance favoring a healthy intestinal flora. 

These two recent studies published in Nature represent a crucial breakthrough, identifying the key immune cell repertories responsible for suppressing the undesired immune response against “good” commensal bacteria in the gut. Scientists now have a clear cellular platform to understand how the immune system learns to tolerate the good intestinal bacteria, and to address a number of crucial mechanistic questions on how Tregs or RORgammat+ ILC emerge in response to the diversity of commensal bacteria, or how changes in gut bacteria diversity throughout life are reflected in the repertoire of Tregs or  RORgammat+ ILC. For example, in light of a chronic intestinal infection, it remains unknown as to whether the chronic existence of these disease-causing bacteria could fool Tregs or RORgammat+ ILCs into recognizing them as “good” bacteria, causing immune-tolerance to bacteria that normally do not belong in the healthy gut flora. Likewise, it remains unclear as to whether the loss of commensal bacterial colonies to intense antibiotic treatment would eliminate the repertoire of Tregs or RORgammat+ ILCs that can recognize these bacteria, and consequently the loss of the immune system’s ability to tolerate these bacterial colonies in the future. Moreover, it remains speculative as to whether Tregs and RORgammat+ ILC represent a part of a redundant fail-safe mechanism to ensure that the immune system does not easily get fooled into tolerating the undesired bacterial colonies in the intestinal tract. 

Indeed, addressing the above possibilities would help to better understand how the healthy bacterial flora in the intestinal tract is maintained by the immune system, and whether intestinal disorders can be triggered by fooling the immune system into tolerating the disruption of the healthy intestinal flora. 

Cebula A., et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature (2013) May 9;497(7448):258-62. doi: 10.1038/nature12079. 
Hepworth R., et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature (2013) doi:10.1038/nature12240.