New Kids on the Block: Type 1 Innate Lymphoid Cells

Mucosal innate lymphoid cells are part of the new frontier of immunology research. Part of the innate immune system, these cells represent the primitive siblings of the more familiar T cells of the adaptive immune system. Without T cell receptors and very responsive to ambient cytokines, they can quickly amplify responses by producing their own effector cytokines. Are these cells behind IBD? New literature suggests that this may be the case.

 

TIBDI blog post 11-01

 

Researchers at the Washington University School of Medicine are currently busy defining subsets of innate lymphoid cells (ILCs). Their most recent finding is the type 1 ILC called, ILC1. Cells with this designation are CD3-CD56+Nkp44+CD103+. To put it simply, this means that it’s not a typical T cell, has characteristics of NK cells and it can be found near epithelial layers. Using material obtained from human tonsils, they were able to determine that these cells could express the high amounts of IFNγ and CCL4 after being exposed to IL-12 and IL-15, and have the kill other cells through both granzymes and perforin.

IL-12 and IL-15 are cytokines that are produced during viral infection. The ILC1’s effector cytokines are in line with this response, CCL4 is used to attract more monocytes and IFNγ activates macrophages and limits viral infection. A co-culture experiment combining the ILC1’s with pathogen stimulated dendritic cells or macrophages further established a viral connection; stimulation with poly I:C, mimicking single strand RNA of viruses, led to great responses while Pam3CSK4, associated with bacterial cell walls, did not.

Although viral infections in IBD are not currently a hot topic, previous research has linked IL-12, IL-15 and IFNγ production to increased severity in many colitis models. Moreover, a recent article has shown that an IL-15 antagonist is effective against symptoms in the dextran sodium sulfate-induced colitis model. Therefore, the jump to examine the role of these cells in IBD is logical. And they saw that CD patients had relatively more of these cells as compared to normal individuals, suggesting an increase. However, they had too few cells to do functional studies.

The final experiments were performed in mice. The murine ILC1s were fairly similar to their human counterparts, expressing IFNγ after exposure to IL-12 and IL-15. To cap off the study, an in vivo experiment they attempted to deplete of these cells using anti-NK1.1 antibody injections combined with the anti-CD40 a colitis model. They saw some success, but nothing radical.

The use of the NK1.1 depletion and the anti-CD40 colitis model raises questions about interpretation. NK1.1 depletes not only ILCs but also NK cells and NK T cells. Therefore, it’s impossible to say precisely which cell type is causing the effects in the model. And, previous studies using the same antibody in other colitis models show that it can sometimes lead to worse disease, suggesting a protective role for the depleted cells.

The anti-CD40 model is also not the best IBD model. CD40 is surface protein expressed on dendritic cells, macrophages and B cells. Its ligand is expressed by activated T helper cells and it allows the T helper cells to communicate danger to them. The model requires that an activating CD40 antibody be injected into Rag-/- mice, which do not have their own T or B cells. The systemic stimulation of CD40 causes massive activation of the dendritic cells and macrophages. Ultimately, this leads to colitis symptoms, but the disease is not representative of IBD being purely caused by the innate immune system. Both the adaptive and innate arms of the immune system are suggested to be involved in IBD. As a result, it’s impossible to make hard conclusions from their in vivo experiment.

As someone who has strong ties to research surrounding the adaptive immune response, I must admit that I find it difficult to surrender the center stage to cells like ILCs. However, the study of ILCs is important to learning about how inflammation propagates. An important issue for the future is finding out the contribution of these cells to chronic inflammation, which will require functional studies to be performed with cells isolated from the colons of human IBD patients. As many researchers know, that’s a tall order.

Let me know what you think about ILCs in IBD! Do you think that they may turn out to be more important than regular T cells?

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

References

Fort, M. M., Leach, M. W., & Rennick, D. M. (1998). A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. Journal of immunology (Baltimore, Md : 1950), 161(7), 3256–3261.

Fuchs, A., Vermi, W., Lee, J. S., Lonardi, S., Gilfillan, S., Newberry, R. D., et al. (2013). Intraepithelial Type 1 Innate Lymphoid Cells Are a Unique Subset of IL-12- and IL-15-Responsive IFN-gamma-Producing Cells. Immunity, 38(4), 769–781. doi:10.1016/j.immuni.2013.02.010

Royer, B. B.-L., Pierroz, D. D., Velin, D., Frossard, C., Zheng, X. X., Lehr, H. A., et al. (2013). Effects of an Interleukin-15 Antagonist on Systemic and Skeletal Alterations in Mice with DSS-Induced Colitis. The American Journal of Pathology, 1–14. doi:10.1016/j.ajpath.2013.02.033

Uhlig, H. H., McKenzie, B. S., Hue, S., Thompson, C., Joyce-Shaikh, B., Stepankova, R., et al. (2006). Differential Activity of IL-12 and IL-23 in Mucosal and Systemic Innate Immune Pathology. Immunity, 25(2), 309–318. doi:10.1016/j.immuni.2006.05.017

Yoshihara, K. (2006). Role of interleukin 15 in colitis induced by dextran sulphate sodium in mice. Gut, 55(3), 334–341. doi:10.1136/gut.2005.076000

 

 

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