A New Subtype of Regulatory T Cell Functions in Intestinal Wound Healing

In reference to a new paper published in Nature Immunology by researchers at King's College London and the National Institutes of Health.

Despite what you might hear in advertisements, “boosting your immune health” isn’t always a good thing. An overactive immune response could contribute to developing an allergy or an autoimmune disease. Excess inflammation can also damage sensitive tissues that aren’t used to that sort of response. A key element in keeping the immune response from getting out of control is the regulatory T cell (T_reg). These are a special subset of T cells, the adaptive immune cells that (along with B cells) allows the body to have stronger, faster immune responses to pathogens that it’s been exposed to in the past. This is accomplished by the manufacturing of memory B and T cells, which are produced during the first immune response and stick around for years after. Some early T cell progenitors will become cytotoxic T cells (CTLs) which kill diseased cells with . Others become helper T cells (T_h), which help determine the type of immune response to use for any given infection. For instance, a T_h1 mediated response will use CTLs and produce more inflammation than a T_h2 response, which limits inflammation and prefers to use antibodies to fight the infection. T_regs, however, reduce the ability of CTLs and other cytotoxic immune cells to kill cells and cause inflammation.  Some T_regs are made in the thymus, while others differentiate from naïve T cells peripherally out in other tissues (Sakaguchi et al. 2008). Their anti-inflammatory action can be performed by the secretion of anti-inflammatory types of chemical messengers called cytokines, specifically TGF- ß and IL-10. T_regs can also interrupt the activation of other T cells by blocking B7, a cell surface marker which needs to bind other cells for the T cells to become activated.

T_regs either develop from T cell progenitors in the thymus or from naïve T cells in the peripheral tissues. They prevent other T cell variants from performing immune functions which may lead to autoimmunity, allergy, and other forms of harmful excessive inflammation (Sakaguchi and Powrie 2007).

In a new study by Povoleri et al., a new type of T_reg was identified. This cell, dubbed a CD161⁺ T regulatory cell for the CD161 cell surface protein which distinguishes from other T_regs, has all the classical features of other T_regs. It expresses similar genes at similar levels, particularly the T_reg-specific protein FoxP3 which is generally thought to designate T cells to differentiate into T_regs (Coffer and Burgering 2004). However, it has subtle differences in its T cell receptor as well as a slightly different combination of cell surface marker proteins. When the researchers compared CD161⁺ T_regs to naïve (not yet activated) and memory (primed and ready to stop inflammation) T_regs, they found the CD161⁺ T_regs were more effective in suppressing CTL activity. The CD161⁺ T_regs were also more useful in preventing the mouse immune system from rejecting tissue grafts, indicating that they suppress the inflammatory response more thoroughly than other T_regs. When each type of T_reg was activated, the CD161⁺ T_regs produced more anti-inflammatory cytokines than either naïve or memory T_regs.

The researchers also found that the CD161⁺ T_regs are regulated by retinoic acid, a molecule that normally causes T_regs to develop in the intestines. Retinoic acid causes the CD161⁺ T_regs to express the CD161 protein as well as the CCR9 and ITGA4 genes, factors that cause cells to move to the intestinal tissues. In addition, the paper examined multiple protein binding sites on the CD161⁺ T_reg DNA and found that binding of the protein BACH2 will decrease expression of many CD161⁺ T_reg-specific genes. In this manner, BACH2 prevents the differentiation of CD161⁺ T_regs from T cell progenitors. Unsurprisingly, CD161⁺ T_regs show very low levels of BACH2 expression. Since other genes like CD161 that are regulated by BACH2 are often involved in wound healing, the authors theorized that CD161⁺ T_regs may play a role in healing wounds in the intestinal tissue that they localize to. 

These suspicions were confirmed when the authors found a higher abundance of CD161⁺ T_regs in the intestinal tissue than either naïve or memory T_regs. This trend was even stronger in individuals with Crohn’s Disease, a condition which causes excessive inflammation in the colon. It is likely that CD161⁺ T_regs are being trafficked to the inflamed tissues created by Crohn’s in order to reduce the inflammation. When wounded colorectal cells were grown in the presence of all three kinds of T_regs, the tissue healed most effectively when CD161⁺ T_regs were added. Taken together, this data all indicates that this new variation of regulatory T cell is vital for healing wounded tissue in the intestines. This could be incredibly useful new information in the fight against diseases like Crohn’s that cause severe pain from excessive inflammation. Perhaps other tissue-specific T_reg subtypes exist that can be used to fight localized inflammation in different regions throughout the body.

References

Coffer, P. J., & Burgering, B. M. (2004). Forkhead-box transcription factors and their role in the immune system. Nature Reviews Immunology, 4(11), 889.

Sakaguchi, S., & Powrie, F. (2007). Emerging challenges in regulatory T cell function and biology. Science, 317(5838), 627-629.

Sakaguchi, S., Yamaguchi, T., Nomura, T., & Ono, M. (2008). Regulatory T cells and immune tolerance. Cell, 133(5), 775-787.