Category Archives: Stem cells

SIRT1 and Stress Suppress Regulatory T Cells

High traffic
Is it actually our stressful lives that are setting the stage for inflammatory bowel disease?
This week on TIBDI: Human stem cell transplantation redefines T cell repertoires, SIRT1 blocks the development of induced regulatory T cells, and stress sets the stage for intestinal inflammation.

Stem Cell Transplantation Wipes CD4+ T cell Memory

Human stem cell transplantation (HSCT) is a potential treatment for severe cases of inflammatory bowel disease (IBD). One way that HSCT works is by resetting the adaptive immune system. However, few studies have looked in depth at changes in the T cell repertoires. Dr. Paolo Muraro from the Imperial College of London has now addressed this question. In a HSCT trial for multiple sclerosis (MS) patients, he and his team used high-throughput sequencing to assess T cell receptor changes in 24 patients. They found that CD4+ and CD8+ T cells responded differently to HSCT. The patients’ CD4+ T cells were redefined and had a new repertoire of clones, while the CD8+ T cells reflected pre-HSCT clones. Resetting CD4+ T cells could be one reason why that HSCT is also successful for IBD.

SIRT1 Suppresses Suppressor Induction

Regulatory T cells (Tregs) are known to be important in IBD, and work from animal models shows that they can regulate the severity of symptoms. Previous work by Dr. Tatiana Akimova and her colleagues at the Children’s Hospital of Philadelphia demonstrated a connection between SIRT1 and Tregs. To investigate this more in induced Tregs, they used SIRT1 deficient cells in the T cell transfer model of colitis. Loss of SIRT1 increased the induction of Tregs and effectively attenuated colitis development. This result was mirrored in dextran sodium sulfate colitis using an inhibitor of SIRT1 (EX-527). It will be interesting in the future to see if targeting SIRT1 will work in a therapeutic setting.

Stress Hinders Regulatory T Cells

Most IBD patients are quite aware that stress plays a role in their disease progression. However, the connection between stress and IBD remains shaky. Dr. Wei Wu of Tongji University considered that the missing link could be Treg function. To test this concept, they stressed mice and investigated the Tregs both in vitro and in vivo. Tregs from stressed mice were unable to function as normal, and some expressed IL-17 and TNFα. Prolactin, a stress mediator, mediated this change via dendritic cells. Stressed mice were highly susceptible to colitis, however, blocking prolactin reduced colitis. The authors feel that stress and prolactin set the stage for IBD development by the conversion of Tregs from effective suppressors to harmful pro-inflammatory T cells.


TCRs in Innate Lymphoid Cells and Epithelial Monolayers

colon and small intestine wall
Functional monolayers of epithelial cells aren’t everything, but they’re a good start.

This week: the use of the TCR in innate-like lymphoid cells is determined; γδ T cells recognize self-lipids, and researchers have developed a technique to create primary epithelial monolayers.

Continue reading TCRs in Innate Lymphoid Cells and Epithelial Monolayers

Immunosuppression with Stem Cells and the Skin Fights Helminths

Mesenchymal Stem Cell
Mesenchymal Stem Cells induce an immunosuppressive response in the colon.
This week, we learn more about how mesenchymal stem cells affect the immune system, why CX3CR1 is needed to clear a yeast infection and how the body stops helminths in their tracks.

Stem Cells and Immunosuppression

A recent study on mesenchymal stem cell (MSC) therapy has uncovered a novel mechanism of immunosuppression in the colon. The French group was using MSC therapy to counter gastrointestinal complications caused during tumor radiotherapy. They found that the treatment reduced colon epithelial damage, but also reduced the relative proportion of infiltrating CD4+ and CD8+ T cells. There was also a marked reduction of T cell activation and proliferation. This downregulation was parallel with significant increases of corticosterone secretion and subsequent interleukin-10 expression.  Experiments with a glucocorticoid receptor blocker pointed towards an impaired TCR signal transduction initiated by the MSC treatment. It will be interesting to see if this finding can help improve MSC treatment of inflammatory bowel disease (IBD).

CX3CR1 and Candida

Crohn’s disease (CD) is often associated with harmful Candida albicans infections. Unlocking the secrets behind how the body controls Candida infections could be beneficial for CD patients. In this study, performed by the NIH, it was determined that the chemokine receptor CX3CR1 is crucial for macrophage survival in the kidney, the preferred hideout for Candida. During an infection, it was found that CX3CR1 was upregulated in the kidney macrophages. Mice deficient in CX3CR1 had a high mortality and were found to have uncontrolled Candida growth in the kidneys. The loss of the receptor prevented macrophages from accumulating in the kidney and engulfing the yeast. Given the growing role CX3CR1 in the pathogenesis of IBD, it will be interesting to consider if this receptor forms a link between CD and associated Candidiasis.

Helminth Induced Immune Reactions

As intestinal worms are becoming a new therapeutic for IBD, it’s interesting to learn about the immune responses that are induced upon their introduction to the body. A Japanese study in the Journal of Experimental Medicine has now shown that the skin does its best to prevent reinfection of Nippostrongylus brasiliensis. This species is similar to Necator americanus, which is used in IBD therapy. These worms enter through the skin. The scientists found that during the first exposure the skin had a limited response. However during a second application, there was a huge immune reaction, which was characterized by cellular infiltrates that trapped the larvae. The key immune cell mediating this trapping was the basophil, which detected worm antigens (bound to antibodies) using FcεRI and elicited the help of macrophages. It will be useful to determine if this process hinders worm treatment in IBD patients who have already had helminth infections.


TNFα Increases Myeloid-derived Suppressor Cells: How Does This Apply to IBD?

How TNFa affects myeloid derived suppressor cellsMyeloid-derived suppressor cells (MDSCs) are the new suppressive darlings of the immunology world. These suppressive cells are created as a result of prolonged inflammation and help limit T cell activities. No surprise that they are now being considered as a potential therapy for IBD and autoimmune disease. But, a recent study points its finger at TNFα as being one of the main culprits leading to MDSC development and treatment with anti-TNFα helps keep them in check. However, this would suggest that anti-TNFα treatment in IBD patients might also curb MDSC development. This doesn’t quite seem to line up.

Today it’s Easter and, given that I am bit backed up on work, I am working on a TIBDI post. It’s actually not that bad, it’s cold outside, and I’m looking at set of particularly interesting articles may lead you to rethink your ideas about IBD.

The main article that I looked at was published in Immunity. The article focuses on cells called myeloid-derived suppressor cells (MDSC). These cells are created from myeloid progenitors under conditions with high amounts of systemic pro-inflammatory cytokines, like IFNγ, IL-6 or TNFα. Under these conditions, myeloid progenitors do not mature to granulocytes, dendritic cells and macrophages. Instead, they become an immature progenitor that has suppressive features.

Their most noted suppressive features are the ability to produce reactive oxygen species and sequester of L-cysteine. This leads to T cell hypo-responsiveness through cell cycle arrest, the lowered expression of the TCR ζ chain, the alteration of the TCR binding site. They are also suspected to prime regulatory T cells.

As these cells come about from prolonged or chronic inflammation, the current studies looking at MDSC assumed that they would be useful for controlling inflammation. The unspoken reason that they do not succeed in their task of controlling chronic inflammation is that conditions causing chronic inflammation are too overwhelming. Indeed, studies looking at MDSC in colitis have suggested this.

One study published in 2008 in Gastroenterology by researchers in Germany showed that chronic enterocolitis caused by the repeated administration of antigen-specific CD8+ T cells to a host mouse led to a chronic form of mild inflammation with the development of MDSCs. In contrast, during acute disease when a single large dose of the antigen-specific CD8+ T cells were given, MDSCs were not developed. However, if the MDSCs were transferred from the chronically sick mice to mice being given acute disease, the MDSC were able to lower the severity. The group even showed that IBD patients had significantly higher amounts of MDSC in blood and that they suppressed T cell activities in vitro.

Another study published in the Journal of Digestive Diseases last year by a group in China also suggested the same thing for another colitis model. They collected MDSCs from mice with established TNBS colitis, which is caused by sensitization and re-challenge to the TNBS hapten. They then transferred these MDSCs to host mice and the TNBS colitis was again induced. These mice were partially protected from the disease. Both of these studies clearly suggest that under the right circumstances, MDSC are beneficial to regulating colitis.

Now getting back to the main article, things start to get confusing. The Israeli group found that TNFα, in particular, helped promote MDSC development in mice during a chronic inflammation model, where mice were repeatedly vaccinated with heat-killed Mycobacterim tuberculosis. In this model, the numbers of MDSCs were raised in the spleen and bone marrow and their production of reactive oxygen species was increased. T and NK cell function was compromised due to the loss of TCR ζ chains

Using a combination of in vitro and in vivo techniques with Tnf-/- mice; doses of Etanercept, which neutralizes TNFα; and MDSC depletion antibodies; they found that they could strikingly reduce the formation of MDSCs and normalize T and NK function. To sum it up, TNFα was responsible for large numbers of highly suppressive MDSCs and using Etanercept helped eliminate them.

This is where things get interesting and confusing. Etanercept is also used to treat a number of chronic conditions like IBD and rheumatoid arthritis. If MDSCs are supposed to be helpful in these conditions, why would their loss be helpful? This result calls into question the actual role of MDSCs in chronic disease.

I think that one of the first steps to find out what is really happening is to see if the numbers of MDSCs are actually lowered in IBD patients after anti-TNFα therapy. Additional steps would be to look at MDSC transfers in chronic models, and not just in acute models of inflammatory disease. All of the studies that I’ve mentioned here only look at the positive benefits of MDSC transfer in acute disease. These models are poor representatives of the inflammatory state in human patients, which have had their diseases for years. The question that needs to be addressed is, are these cells helping or hindering chronic autoimmune diseases?

What do you think? Do you think that the Immunity article should cause researchers to question the use of MDSC for treating chronic disease? Let me know in the comments below.

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


Bronte, V., & gabrilovich, D. (2010). Myeloid-derived suppressor cells. (K. Minton & O. Leavy, Eds.) Nature Reviews Immunology.

Haile, L. A., Wasielewski, von, R., Gamrekelashvili, J., Krüger, C., Bachmann, O., Westendorf, A. M., et al. (2008). Myeloid-Derived Suppressor Cells in Inflammatory Bowel Disease: A New Immunoregulatory Pathway. Gastroenterology, 135(3), 871–881.e5. doi:10.1053/j.gastro.2008.06.032

Sade-Feldman, M., Kanterman, J., Ish-Shalom, E., Elnekave, M., Horwitz, E., & Baniyash, M. (2013). Tumor Necrosis Factor-α Blocks Differentiation and Enhances Suppressive Activity of Immature Myeloid Cells during Chronic Inflammation. Immunity, 38(3), 541–554. doi:10.1016/j.immuni.2013.02.007

Su, H., Cong, X., & Liu, Y. L. (2012). Transplantation of granulocytic myeloid derived suppressor cells (G-MDSCs) could reduce colitis in experimental murine models. Journal of Digestive Diseases, n/a–n/a. doi:10.1111/1751-2980.12029

One T Cell to Rule Them All

Ly6B staining during colitis
Inflamed Colon with Stained Neutrophils

In the last post, we discussed a bit about how some stem cells are able foster memory T cells, which contribute to the chronicity of colitis. This time, I look at an article that sheds even more light on the role of the bone marrow during inflammation. It was found that under conditions of inflammation, stem cell number increase. During colitis, these cells proliferate and, ultimately, produce more neutrophils and macrophages.

Main points:

  • Hematopoietic stem cells and progenitor cells can be found outside the bone marrow during inflammation in the colon.
  • This appeared to be mediated by T cell-derived cytokines.
  • This process increased the amounts neutrophils and macrophages at the sites of inflammation.

Take home message: In light of my last post, T cells can profoundly influence the innate immune system through stem cells. This strengths their potential role in chronic inflammation.

Neutrophils and macrophages are directly involved in causing damage in the colon during inflammation. Neutrophils and macrophages are the tanks of the immune system and each has their own weapon. Neutrophils are capable of releasing granules containing harmful reactive oxygen species and enzymes. They also release microbial webs (à la Spiderman). Macrophages engulf harmful bacteria and other pathogens and then secrete cytokines (chemical messengers) that alert other immune cells.

The authors used mainly the T cell transfer colitis model, induced by transferring CD4+CD25-CD45RBhi T cells (naïve T cells) to Rag1-/- mice (mice lacking T cells). They found that the inflammatory environment created by T cell transfer colitis had an effect on hematopoietic stem cells (HSC) in the bone marrow (BM), causing them to proliferate. HSC are the stem cells that produce immune cells. The developmental process involves first the production of multipotent progenitor cells. These HSC daughters have a limited life span, but are capable of further differentiating into two types of progenitors, the myeloerythroid progenitors (CMPs) or common lymphoid progenitors (CLPs). CMPs can further differentiate into either megakaryocyte-erythroid progenitors (MEPs) or granulocyte-monocyte progenitors (GMPs). The authors found that under conditions of inflammation, the GMPs would begin to dominate the total myeloid progenitor population. Moreover, HSC and GMP were also found outside of the bone marrow in the spleen and even in the inflamed colon.

IFNg and GM-CSF were considered possible candidates for the induction of these changes. IFNg is produced mainly by T cells and is important in supporting a Th1-associated immunity and is also known to directly affect HSC function. When the authors neutralized IFNg in vivo with antibodies, they found that the proliferation of the HSC decreased considerably. GM-CSF, on the other hand, is produced by stromal cells in the bone marrow (e.g. fibroblasts) and can also be produced by Th17 cells.  GM-CSF is known to be involved with the differentiation of granulocytes. When this cytokine was neutralized, there was little effect on the HSCs, but instead an effect of the downstream GMPs. They were less dominant and loss of GM-CSF reduced their ability to populate the spleen and the colon during colitis.

One point that the authors wished to make was that IL-23 was involved in their findings. This is because IL-23 has such a prominent role in IBD pathogenesis. Current studies looking at genetic association in IBD show that many genes involved in IBD have something to do with the IL-23 pathway. To make this point, they emphasized that in the T cell transfer model many of the transferred T cells eventually differentiate into Th17 cells that require IL-23 for maintenance. They also looked at a form of colitis induced by H. hepaticus infection of 129SvEv.Rag2-/- mice (mice lacking T cells) that is mediated via IL-23. They found that this model also displayed inflammation-associated changes in HSCs; abundant and proliferating HSCs were evident and neutralizing IFNg reversed the phenotype. They also looked at T cells isolated from both wildtype and IL-23R-/- mice and found that Th17-derived GM-CSF was at least partially dependent on IL-23R expression on T cells. However, the most convincing evidence was that IL-23-/- mice with T cell transfer colitis showed reduced GMP accumulations.

I find the IL-23 point in this article not particularly exciting. What I do like is the concept of T cell-derived GM-CSF and IFNg being so important in encouraging the production of excess GMPs during inflammation, though the authors didn’t actually prove this. Still, if you consider these findings together with my last post, which discussed how IL-7 is necessary for T cell transfer colitis by creating a niche for colitogenic memory T cells, it would almost seem that the MSCs (via IL-7) of the bone marrow are controlling inflammation by supporting memory T cells that can provide crucial information to the HSCs. The T cells “communicate” to the HSCs via IFNg that supports of HSC proliferation and mobilization to peripheral regions. GM-CSF would then provide an additional signal to encourage the differentiation of GMPs and, ultimately, the increase of neutrophils and monocytes.

In light of the last post, it seems that there is an intimate relationship between the stem cells of the bone marrow and T cells during colitis development. Naturally, the question is, which cells are more important in generating inflammation in the colon, the T cells or the stem cells? In other words, which cell really does rule them all?

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


Griseri T, McKenzie BS, Schiering C, Powrie F. Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin-23-driven chronic intestinal inflammation. Immunity. 2012 Dec 14;37(6):1116-29. doi: 10.1016/j.immuni.2012.08.025. Epub 2012 Nov 29.