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.
- Jiang, W., Wang, X., Zeng, B., Liu, L., Tardivel, A., Wei, H., et al. (2013). Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. The Journal of experimental medicine, 25(6), 496. doi:10.1073/pnas.0700822104
- VanDussen, K. L., Liu, T.-C., Li, D., Towfic, F., Modiano, N., Winter, R., et al. (2013). Genetic Variants Synthesize to Produce Paneth Cell Phenotypes that Define Subtypes of Crohn’s Disease. Gastroenterology, 1–54. doi:10.1053/j.gastro.2013.09.048
- Zhang, N., & Bevan, M. J. (2013). Transforming Growth Factor-beta Signaling Controls the Formation and Maintenance of Gut-Resident Memory T Cells by Regulating Migration and Retention. Immunity, 1–10. doi:10.1016/j.immuni.2013.08.019