A new NIAID study explains how naturally occurring gut bacteria contribute to disease severity in a mouse model of arthritis. Understanding how gut microbes regulate immune cells will help researchers identify how autoimmune disorders like arthritis develop. The study appears in the June 27, 2013, online issue of Immunity.
Autoimmune disorders occur when the immune system attacks the body’s own cells, tissues, and organs. Immune cells called self-reactive T cells can be responsible for these attacks. Normally, self-reactive T cells are present in the body but exist in a hibernation-like state. However, in autoimmune diseases, self-reactive T cells are easily activated, or awoken, and researchers are trying to understand how this change occurs.
For years, scientists have known that bacteria naturally found in the gut can have profound effects on the development and activity of immune cells. Scientists also know that specific bacteria in the gut, such as segmented filamentous bacteria (SFB), can worsen the development of diseases like autoimmune arthritis in mice. However, it was unknown if or how gut bacteria influenced the activation of self-reactive T cells.
NIAID researchers Pascal Chappert, Ph.D., and Ronald Schwartz, M.D., Ph.D., proposed that specific gut bacteria could increase the sensitivity of self-reactive T cells, enhancing their activation in autoimmune disease. To test this concept, they used a mouse model of arthritis that is driven by self-reactive T cells. While monitoring disease progression in two groups of mice that harbored different gut bacteria, they observed that one group consistently had more severe arthritis than the other. They also discovered that SFB were responsible for this worsening of disease.
The researchers then identified specific steps that linked SFB to severe autoimmunity. First, mice with SFB produced more IL-12p70, a pro-inflammatory cytokine, in the gut. T cells are activated by various signals, including pro-inflammatory cytokines. Second, mice with SFB had higher numbers of self-reactive T cells. A key feature of activated T cells is their ability to divide and increase in number.
The researchers found that SFB could change the activation threshold of self-reactive T cells through the stimulating properties of IL-12p70. Because the T cells were now more sensitive to additional activating signals, they increased in cell number and produced more IFN-γ, another pro-inflammatory cytokine, which drove disease severity.
The NIAID researchers demonstrate that changes in the microenvironment caused by gut bacteria can trigger T cells to alter their activation threshold. This work provides key information in understanding how gut microbes affect immune cells, which may help scientists design better therapies for autoimmune disease or conversely, strengthen immune responses in immune-deficient patients.
Chappert P, Bouladoux N, Naik S, Schwartz RH. Specific gut commensal flora locally alters T cell tuning to endogenous ligands. Immunity (2013)
Last Updated June 25, 2013