Are Regulatory T Cells Defective in Crohn’s Disease?

256px-Healthy_Human_T_Cell
T lymphocyte by NIH (public domain)

My own research experience with regulatory T cells (Tregs) always makes me sensitive to any articles exploring their function in IBD. This week was no exception. Researchers from Denmark have noticed that Tregs are dysfunctional in a unique mouse model of CD; one that uniquely mimics the inflammatory pathology typically found in the terminal ileum.

The mouse model in question is the SAMP1/YitFc (SAMP) model of ileitis. It is a spontaneous model requiring no additional treatments to cause the disease to appear. “SAM” stands for senescence accelerated mice and the final “P” represents prone. Interestingly, this particular strain of mouse was derived from a mouse that had a shortened lifespan. This characteristic is, however, no longer apparent in this strain. Instead, the main pathology is an ileitis that is strikingly similar to Crohn’s disease with skip lesions, transmural inflammation and scarring that can lead to stricture formation.

The precise genetic elements that cause the SAMP mouse to be so susceptible to colitis are unknown. Many tout it as being truly spontaneous, but that is unlikely seeing that the disease penetrance of the mice is so high. Genome wide scans have uncovered several possible genes that may be involved including the anti-inflammatory IL-10 receptor; the pro-inflammatory cytokine, IL-18; the transcription factor, PPARγ and several genes involved with intestinal barrier function. However, the defect is known to lie in the non-hematopoietic cells (cells not derived from the bone marrow).

The researchers looked at the role of Tregs using a simple technique of injecting depleting antibodies for the marker, CD25. CD25 is part of the IL-2 receptor and is highly expressed on Tregs. They found that not only did the SAMP get more severe ileitis, but also transfer of Treg-depleted T helper cells to severe combined immunodeficient (SCID) mice caused an even stronger colitis than would be normally expected from wild type mice. Transfer of CD4+CD25- T helper cells into SCID mice is a well-known method of inducing colitis.

Further experimentation revealed that the Tregs isolated from the SAMP mice, while being suppressive in vitro, were unable to prevent the colitis caused by the transfer of non-Treg into the SCID mice; something that is easily accomplished by Tregs isolated from wild type mice. These Treg were also different from the wild type versions in that they produced high amounts of cytokines that are normally associated with T helper 1(Th1) and T helper 2(Th2) responses.

Not mentioned in the abstract were results shown in the last figure. The authors found that SAMP mice have a severe loss of IL-17 producing T cells (Th17). Th17 cells are currently considered the bad guys of IBD. The fact that SAMP mice have reductions in these cells does go against the current ideas. It isn’t surprising that they weren’t advertising this result.

The authors wondered if defective Treg could be one of the problems in Crohn’s disease (CD) patients. Other researchers have isolated Tregs from CD patients and have seen that they retain their functionality in vivo, however, they also accumulate at the sites of inflammation in the mucosa; apparently being unable to resolve active inflammation. There is a possibility that CD patients, like the SAMP mice, have Tregs that are unable to perform their function properly in vivo. If this is the case, then steps can be made (like Treg transfers) to remedy the situation.

I have my doubts about the idea that Tregs are defective in CD patients. Although, it is an attractive concept, I feel there are so many more issues that need to be clarified. The loss of the Th17 cells could also be extremely important. Without Th17, there will be difficulties controlling microbiota (studies looking at the microbiota in SAMP have yet to be done). There is literature showing that germ-free SAMP mice have less disease and that probiotics can also limit severity.

I would enjoy hearing your thoughts regarding the similarities between CD patients and SAMP mice. Please don’t hesitate to discuss your ideas in the comments section.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.

References

Ishikawa, D., Okazawa, A., Corridoni, D., Jia, L. G., Wang, X. M., Guanzon, M., et al. (2012). Tregs are dysfunctional in vivo in a spontaneous murine model of Crohn’s disease. Mucosal Immunology, 6(2), 267–275. doi:10.1038/mi.2012.67

Kelsen, J., Agnholt, J., Hoffmann, H. J., Romer, J. L., Hvas, C. L., & Dahlerup, J. F. (2005). FoxP3+CD4+CD25+ T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn’s disease. Clinical and Experimental Immunology, 141(3), 549–557. doi:10.1111/j.1365-2249.2005.02876.x

Pizarro, T. T., Pastorelli, L., Bamias, G., Garg, R. R., Reuter, B. K., Mercado, J. R., et al. (2011). SAMP1/YitFc mouse strain: A spontaneous model of Crohn’s disease-like ileitis. Inflammatory Bowel Diseases, 17(12), 2566–2584. doi:10.1002/ibd.21638

Saruta, M., Yu, Q. T., Fleshner, P. R., Mantel, P.-Y., Schmidt-Weber, C. B., Banham, A. H., & Papadakis, K. A. (2007). Characterization of FOXP3+CD4+ regulatory T cells in Crohn’s disease

. Clinical Immunology, 125(3), 281–290. doi:10.1016/j.clim.2007.08.003

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