Molecular Pathway Discovery May Help Treat Psoriasis, Crohn’s Disease, Arthritis

Dec 26, 2013 by Sci-News.com

A team of scientists at Sanford-Burnham Medical Research Institute has found a new molecular pathway that rebalances the immune system by turning down inflammatory T-cell responses.

Sanford-Burnham Medical Research Institute researchers found that retinoid-related orphan receptor gamma-t (RORγt) and interleukin-7 (IL-7) influence gamma-delta T-cell homeostasis and function by regulating expression of the inhibitory receptor, B and T lymphocyte attenuator (BTLA). Image credit: Bekiaris V et al

Sanford-Burnham Medical Research Institute researchers found that retinoid-related orphan receptor gamma-t (RORγt) and interleukin-7 (IL-7) influence gamma-delta T-cell homeostasis and function by regulating expression of the inhibitory receptor, B and T lymphocyte attenuator (BTLA). Image credit: Bekiaris V et al

Using a combination of human cells and a mouse model of psoriasis, the team led by Prof Carl Ware identified the B and T lymphocyte attenuator (BTLA) inhibitory receptor as a key factor in limiting inflammatory responses, particularly in the skin.

“Our study shows that BTLA expression in gamma-delta T-cells deactivates their response to immune stimuli,” Prof Ware said.

“Gamma-delta T-cells are the first line of defense against pathogens – and unless ‘turned off’, can lead to unwanted inflammation and tissue destruction.”

Until now, scientists knew that gamma-delta T-cells were important for initiating inflammatory responses in the skin, but not how to turn off these potent cells.

Prof Ware’s study showed that the retinoid-related orphan receptor gamma-t (ROR gamma-t) nuclear transcription factor works with interleukin (IL)-7, to coordinate the expression of BTLA, which in turn regulates gamma-delta T cell responses to inflammatory stimuli.

The study found that ROR gamma-t works to inhibit BTLA transcription, thereby limiting its availability in gamma-delta T-cells. This allows the expansion of T-cell numbers and their production of inflammatory cytokines, including IL-17 and TNF.

In contrast, IL-7 increases the availability of BTLA on the cell surface, reducing the number of active T cells and allowing BTLA to rein in the immune response.

“To be effective against pathogens, yet prevent damage from the body’s own defenses, the immune system has to maintain a balance. In essence, BTLA helps control inflammatory responses by reducing the activity and numbers of active gamma-delta T cells,” Prof Ware said.

The results, published in the journal Immunity, could help scientists develop new treatments for inflammatory disorders such as psoriasis, Crohn’s disease and arthritis by targeting BTLA to reduce inflammation, promote homeostasis, and control disease.

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Bekiaris V et al. 2013. The Inhibitory Receptor BTLA Controls γδ T Cell Homeostasis and Inflammatory Responses. Immunity, vol. 39, no. 6, pp. 1082-1094; doi: 10.1016/j.immuni.2013.10.017