Tag Archives: Paneth cells

Controlling Intestinal Lymphocytes and Abnormal Paneth Cells

Complete intestinal metaplasia in a case of chronic gastritis, HE 3
Paneth cells, the red cells in the crypts, become abnormal in Crohn’s patients with NOD2 and ATG16L1 mutations.
This week, there are interesting insights about intestinal lymphocyte population maintenance with exciting functions for TGFβ and NOD2. Also a unique perspective uncovers relationships between Crohn’s disease mutations and Paneth cell function.

TGFβ-directed Memory Retention

Memory; it’s the characteristic of the adaptive immune system that allows it to react quickly and specifically. Resident memory CD8+ T cells (Trm) found in the intestines are a valuable subset of cytotoxic T cells that defends against intestinal viral pathogens. However, the signals that mediate this population were unclear. The recent article by Zhang and Bevan sheds some light on how this works. To do this, they created a transgenic mouse with TCRs specific for a model virus and lacking a transforming growth factor (TGF)-β receptor. With this unique tool, they were able to determine that TGFβ plays two important roles for Trm during inflammation. 1) It inhibits the migration of dividing CD8+ T cells from the secondary lymphoid organs during the beginning of inflammation, and 2) it helps retain the same cells in the intestines during the later stages of inflammation.

NOD2 Maintains Intraepithelial Lymphocytes

Despite the association between NOD2 and Crohn’s disease being known for more than ten years, how NOD2 functions in the gut is only now be unraveled. In a recent article in the Journal of Experimental Medicine, it was found that Nod2 deficient mice lack intraepithelial lymphocytes (IELs). IELs are mainly CD8+ T cells and γδ+ T cells and appear to have a protective role in inflammatory bowel diseases. The loss was mediated largely by deficiencies in proliferation and survival. Further investigation revealed that Nod2-microflora interactions were required along with Nod2 signaling on antigen presenting cells and interleukin-15 production to have optimal populations of IELs and protection from colitis.

Crohn’s Mutations and Paneth Cell Phenotypes

Genome wide association scans are an interesting way to learn more about diseases like Crohn’s disease. However, they provide an enormous amount of data. To gain a clearer view of the possible effects of associated mutations, VanDussen et al decided to narrow their scope and focus only on the function of Paneth cells. Paneth cells are the gatekeepers of the intestinal crypts and produce anti-microbial peptides to control bacteria infiltration. The researchers observed that high numbers of defect alleles for NOD2 and ATG16L1 led to high amounts of abnormal Paneth cells in Crohn’s disease patients. This was also associated with altered immune activation, changes in granuloma numbers and disease recurrence.


The Curious Case of Toxoplasma gondii in Intestinal Disorders

T. gondii, a protozoan carried by cats, is known to reside in humans as well. At least 1/3 of the human population carries the cysts without even knowing it. Recent studies have shown that many more IBD patients than healthy individuals carry antibodies recognizing this pathogen, suggesting a possible association in some way. Moreover, current studies in mice show that T. gondii can wreak havoc in the intestines during initial exposure to the parasite leading to the loss of Paneth cells.  As Paneth cells are crucial for keeping intestinal bacteria under control, their loss also leads to an overgrowth.

Main points:

  • T. gondii antibodies are found in IBD patients.
  • T. gondii via TLR11 causes T cells to release huge amounts of IFNγ that leads to the death of Paneth cells in mice.
  • The loss of Paneth cells leads to changes in the microbiota and intestinal inflammation.
  • Humans do not express TLR11, but they could recognize T. gondii via TLR7 or TLR9.

Take home message: The possibility exists that T. gondii infections could complicate or even help initiate IBD in certain individuals.

A recent Journal of Autoimmunity article found that antibodies directed towards T. gondii were more prevalent in IBD patients than in controls. This suggests that T. gondii, a primitive protozoan, could be involved in the pathology of IBD. As up to 1/3 of the human population is often latently infected with T. gondii, this sparked my interest and a quick look at the recent literature about T. gondii revealed that this protozoan isn’t going unnoticed in the intestines (at least in mice that is…).

TIBDI post 4 finalT. gondii is well known for its ability to be spread through cat feces. Indeed, cats are its primary host and is the only mammal in which it reproduces (produces oocysts). T. gondii’s lifecycle consists of first being excreted as an oocyst in cat feces, which are, through various means, ingested by other mammals. In mammals, other than cats, T. gondii can survive as cysts within nervous or muscle tissue, often without the host noticing anything. Mice, which are considered secondary hosts, do not secrete the oocysts in their feces, but are great spreaders of T. gondii because the cysts they carry in their bodies can infect cats when they are caught and eaten.

Mice are efficient at keeping the latent T. gondii under control and show no signs of the infection. However, during acute toxoplasmosis, they do develop an acute immune response that, interestingly enough, includes an intestinal dysbiosis, especially in the area of the ileum.

It is this intestinal pathology that was the focus of a recent article found in Nature Immunology. The authors were interested in finding out more about the immune processes associated with the development of the intestinal disorder. They discovered that the pathology was related to the production of IFNγ by T cells, particularly CD4+ T cells, which would lead to the destruction Paneth cells.

Paneth cells are particularly important cells found in the crypt regions of the intestines. They produce anti-microbial peptides, which keep the crypts free of bacteria. If they die, then intestinal bacteria are free to enter the deep folds of the intestinal surface. This can lead to unwanted interactions between bacteria and bacterial sensing receptors (such as Toll-like receptors (TLRs)) and can, ultimately, cause inflammation.

In the case of the T. gondii-infected mice, it appears that this is happening, and it is a part of the reason that the intestinal problems occur. Their results indicated that recognition of T. gondii through a MyD88 (an adaptor molecule for TLR signaling) dependent cascade in T cells caused a huge release of IFNγ that lead to mitochondrial-damage-induced death of Paneth cells. The loss of these Paneth cells then caused the loss of crucial anti-microbial peptide production and subsequent bacterial over growth. In this environment, they detected that the intestinal flora composition changed and was predominated by the Enterobacteriaceae family of Gram-negative bacteria. These bacteria were not bystanders and their presence was necessary for the intestinal symptoms including the loss of Paneth cells.

This story is fascinating, but has a chicken and the egg problem. If Enterobacteriaceae bacteria are necessary for the loss of Paneth cells, how can it be necessary that the loss of Paneth cells is needed for their abnormal overgrowth? It must be that the combination of T. gondii infection plus normal interactions with Enterobacteriaceae is causing the problem.

The authors do address this somewhat in the discussion and say that it must be a combination of activation of TLR11 and other TLRs that is doing the trick. TLR2, which recognizes Gram-negative bacteria, would be such a candidate. They do find that TLR11-/- mice are partially protected from the intestinal problems, suggesting that TLR11 plays a predominant role. However, they do not check to see if TLR11 is actually the main TLR being triggered on the T cells or even investigate its expression on different immune cells.

Incidentally, TLR11 is not even produced in humans, which would make one wonder how relevant this study actually is for humans. In fact, a recent study in Cell Host & Microbe explains that two alternative TLRs in mice, 7 and 9, recognize RNA and DNA of T. gondii, respectively. They also found that in human cells, this method of T. gondii recognition via nucleic acids is particularly potent.

It is interesting to consider that T. gondii may play a role in IBD. However, intestinal problems are not the most common symptom for human infected with T. gondii. Though the number of IBD patients producing antibodies that recognize T. gondii is significantly higher than healthy controls, the number is still very low (8% of patients react to T. gondii as opposed to 1% in the normal population). Still, it could be that those 8% have just the right genetic background that when exposed to T. gondii produces just the right conditions for the disease to develop. Only further research will answer that question.

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


Andrade, W. A., do Carmo Souza, M., Ramos-Martinez, E., Nagpal, K., Dutra, M. S., Melo, M. B., et al. (2012). Combined Action of Nucleic Acid-Sensing Toll-like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice. Cell Host & Microbe, 1–12. doi:10.1016/j.chom.2012.12.003

Raetz, M., Hwang, S.-H., Wilhelm, C. L., Kirkland, D., Benson, A., Sturge, C. R., et al. (2012). Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-gamma-dependent elimination of Paneth cells. Nature Immunology, 1–9. doi:10.1038/ni.2508

Shapira, Y., Agmon-Levin, N., Selmi, C., Petríková, J., Barzilai, O., Ram, M., et al. (2012). Prevalence of anti-toxoplasma antibodies in patients with autoimmune diseases. Journal of Autoimmunity, 39(1-2), 112–116. doi:10.1016/j.jaut.2012.01.001