Notch for Oral Tolerance and Integrin Targeting in Crohn’s Disease

This week on TIBDI! Notch signaling is needed for the development of antigen sampling macrophages, and blocking integrins on T cells leads to less migration and colitis.

Macrophage
Notch signaling appears to be necessary for the development of cells that sample luminal antigens.
Notch and Intestinal Antigen Samplers

Recent literature has brought to light that macrophage-like cells expressing the chemokine receptor CX3CR1 and the integrin CD11c are needed to continually survey the antigen contents of the intestinal lumen. However, very little was known about how these cells develop. In a new publication, Dr. Chieko Ishifune of The University of Tokushima Graduate School in Japan shows that Notch signaling is involved. The Notch family is a highly conserved set up receptors designed for local cell communication, and they are involved in immune cell development. Using targeted knock-out mice, the researchers found that the downstream transcriptional regulator Rbpj was necessary for CD11c+CX3CR1+cells. Moreover, Notch1 and Notch2 were also needed. These results will help scientists learn more about oral tolerance, which could play a role in IBD.

Integrin Targeting Supported for Crohn’s Disease

The integrin α4 is suspected to be important for the recruitment of T cells to intestinal tissues. This concept is supported by the success of two blocking antibodies, Natalizumab and Vedolizumab, in Crohn’s disease (CD) clinical trials. To precisely examine the role of integrins on T cells during colitis, Dr. Elvira Kurmaeva of Louisiana State University Health Sciences Center transferred CD4+ T cells with a targeted deletion of α4 or β1 to induce colitis in immunodeficient mice. Her results indicated that loss of α4β7 lowered colitis severity. Further analysis of the colons showed that the mice had lower amounts of infiltrating CD4+ T cells, which matched results found in CD patients treated with Natalizumab. Interestingly, the migration problems were only apparent during inflammation, and didn’t affect T cell polarization.

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