Tag Archives: IL-7

Diet in IBD and Gut Antigen Collection Explained

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An animal-based, high fat diet can lead to microbiota changes that may increase IBD development.
This week on TIBDI: Macrophages and dendritic cells work together to collect antigens in the gut, diet could influence inflammatory bowel disease development, and interleukin-7 maintains natural killer T cells.

Capturing Antigen Takes Two in the Gut

Oral tolerance, immune tolerance against ingested antigens, may influence the chronic nature of inflammatory bowel disease (IBD). Finding out how antigen is picked up in the gut and presented to T cells to initiate regulatory mechanisms could lead to new therapies. Now Elisa Mazzini of the European Institute of Oncology in Italy has found that in the small intestine antigen uptake leading to oral tolerance requires teamwork between macrophages and dendritic cells. Macrophages expressing the chemokine receptor CX3CR1 were exceptional in collecting soluble antigens by sticking dendrites between epithelial cells towards the lumen. They then transferred their antigen loads to neighboring dendritic cells expressing CD103, which have the abilities to initiate oral tolerance. Dr. Mazzini found that the transfer required the expression of the gap junction protein connexin 43, which allowed appeared to allow the transfer of entire peptide-MHC complexes.

Diet in IBD

The populations of microorganisms in the human gut are known to change during IBD. However, it’s unknown if there are specific changes that could initiate IBD development. A study by Dr. Lawrence A. David from Harvard University shows how easily the intestinal microbiota is changed by diet. Volunteers on an animal-based diet had significant changes in their populations as soon as one day after the diet reached the gut. Moreover the gene expression and activity of the intestinal residents were also altered. Those with an animal-based diet had increases in Bilophila species, which is associated with the development of intestinal inflammation in mice. The authors suggest that animal-based diets could contribute to the development of IBD.

IL-7 and NKT Cell Survival

Interleukin (IL)-7 is a cytokine that helps the long-term survival of Th17 cells and innate lymphoid cells that express the transcription factor RORγt. It is suspected to be important for maintaining populations of T cells that induce and propagate IBD. Dr. Kylie Webster from the Garvan Institute in Australia has now increased IL-7’s circle of influence. She found that IL-7 also maintains natural killer T (NKT) cells that produce IL-17. IL-7, using the PI3K/AKT/mTOR pathway. IL-7 caused the NKT cells to proliferate in vivo. Because more IL-7 is produced in response to bacterial triggers. Dr. Webster speculated that NKT cells may use IL-7 to quickly respond to bacterial pathogens.


Macrophages Encourage Autophagy and Are Hindered by IL-10

Macrophages could play a key role in the initiation of IBD.
This week on TIBDI: Macrophages are reined in via their IL-10 receptors, Macrophage derived Wnt1 encourages epithelial autophagy, and γδ T cells are controlled by BTLA and IL-7.

Continue reading Macrophages Encourage Autophagy and Are Hindered by IL-10

IBD and T cells: It’s all about memory!

Researchers are getting closer and closer to finding out which immune cells are responsible for the chronicity of IBD. It looks like they might be memory T cells. These cells are long lived and they are the same cells, which make vaccines effective. They are specialized in reigniting an immune response after they come in contact with a pathogen that they recognize. In IBD, it’s not known what they are reacting against; it could be a pathogen or it could be something harmless that the body mistakenly thinks is harmful.

Main points:

  • CD73 can be used as marker for memory T cells in IBD patients.
  • In IBD patients, CD73+ cells also produce IL-17A.
  • Stem cell derived IL-7 is needed in mice for the survival of memory T cells that cause colitis.
  • T cell glycomes influence T cell activation and, thus, colitis in mice.

Take home message: Modulating IL-7 and/or a T cell’s glycome could influence T cell activity in IBD.

Researchers have now found new ways to detect these cells in patient blood and other researchers, using mouse models of IBD, have found out a factor needed for IBD memory T cell survival called interleukin-7. Even more exciting, another group of scientists found out that certain carbohydrate structures, bound to the surface of the memory T cells, can cause the cells to be even more potent than normal. Both of these discoveries offer new ways to treat IBD. Either by eliminating the factor maintaining these cells or by altering the carbohydrate structures on the memory T cell surface.

The role of T cells in IBD is somewhat of a mysterious thing. Certainly they must be involved. There are T cell-dependent colitis models, for instance, and anti-TNFa works in part via T cell apoptosis. Furthermore, memory T cells appear to be the perfect vehicles to propagate chronicity. Why not then? The problem comes from the lack of real evidence showing that this is actually the case. In fact, the concept is just gaining momentum. To give you a taste of the current ideas surrounding memory T cells in IBD, we’ll be discussing three recent articles looking at the subject.

The first article was published in the European Journal of Immunology. This article focuses on human data and will set the stage for this post. In this article, they found that the ectonucleotidase, CD73, was found on T cells in active IBD patients. What makes these cells interesting, is not so much the new marker, but the fact that they also found that these cells were CD45ROhigh, thus memory T cells. Even better, they found that these cells were also IL-17A+ (using intracellular cytokine staining) and expressed high amounts RORC mRNA. These cells were also sensitive to anti-TNFα and were significantly reduced in patients after treatment.

Looking at this study, I was left with a lot of questions about memory T cells function and development. It was time to head to the mouse publications to find out more.

One group examined how colitis-associated memory T cells form and what they need for long-term survival. In a recent Gut publication, this was investigated and it seems that IL-7 is a crucial factor. Using bone marrow chimeras made from knockout mice, the researchers were able to determine that IL-7 produced in the bone marrow is necessary for the development of CD4+CD45RBhigh transfer colitis. No IL-7, no colitis. They then looked for the bone marrow cell that was the culprit. This turned out to be mesenchymal stem cells (MSC), which they confirmed with in vitro and adoptive transfer studies. Co-culture of MSC with memory T cells helped them survive in vitro conditions and transfer of MSC back to mice deficient of IL-7 allowed them to be again susceptible to CD4+CD45RBhigh transfer colitis.

Another way of approaching the memory T cell issue is to look at their functionality and the factors that make them behave the way that they do. One of these factors seems to be the kind of carbohydrates found on the cell surface or what is now called the “glycome.” A Journal of Experimental Medicine article describes that under inflammatory conditions, found locally in the intestines during colitis, a unique glycome arises, which they call the colitis-associated glycome or CAG.

I am not much of an expert regarding glycans, but what is special about CAG is that there is an increase in core 1-expressing O-glycans and a reduction in core 2-expressing O-glycans. Core 1 and core 2 refer to the number of N-acetyl-galactosamine anchors bound to a serine or threonine amino acid of a protein and this determines if one or two sugar chains will be attached respectively. In any case, this CAG is caused by a loss of the enzyme, core-2 b1,6-N-acetylglucosaminyltransferase 1 (C2GnT) and they found that just replacing the enzyme was enough to reduce colitis in the CD4+CD45RBhigh transfer colitis model.

How does this work? They found that the CAG allowed the binding of galectin-4 to the cell surface and this stabilizes lipid rafts, which are the supports for immunological synapses. Immunological synapses could be described as the T cell-APC “kiss” leading to T cell activation. A good kiss, as we all know, leads to better activation (and proliferation). Looking downstream at the signaling cascade, they found that this had to do with increased stability of protein kinase Cq. Some might remember that PKCq is essential for Ca2+ influxes and diacylglycerol production, secondary messengers necessary for the activation of the transcription factors, NF-kB and AP-1.

Putting this together with the above study, I can see possible treatments arising that involve neutralizing IL-7 or increasing C2GnT levels. Treatment efficacy could be monitored by looking at CD4+CD73+ T cells in the periphery (if, of course, this all applies to humans).

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


Doherty GA, Bai A, Hanidziar D, Longhi MS, Lawlor GO, Putheti P, Csizmadia E, Nowak M, Cheifetz AS, Moss AC, Robson SC. CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease. Eur J Immunol. 2012 Nov; 42(11):3062-72. doi: 10.1002/eji.201242623.

Nemoto Y, Kanai T, Takahara M, Oshima S, Nakamura T, Okamoto R, Tsuchiya K, Watanabe M. Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells. Gut. 2012 Nov 9. [Epub ahead of print]

Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A. Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells. J Exp Med. 2012 Dec 3. [Epub ahead of print]