CD1a: a novel target for IL-17-mediated inflammatory skin and gut diseases

Winau, Florian

Abstract

We propose to investigate the function of the lipid-presenting molecule CD1a in Poison Ivy contact dermatitis, as well as psoriasis-like skin inflammation. For this purpose, we will use CD1a-transgenic mice since CD1a is normally lacking in rodent animal models. These experiments will provide the first in vivo evidence that CD1a on Langerhans cells is essential to regulate skin inflammation. Moreover, we will analyze antigen specificity, tropism, and memory of CD1a-restricted T cells. For this purpose, we plan to generate new tools such as CD1a tetramers and novel techniques for lipid loading of CD1a molecules. Lastly, we will develop new kinetic measurements for binding of lipids to CD1a. These studies will reveal the entity of new lipid antigens, such as urushiol, and their role in CD1a-mediated immune responses. In steady-state, CD1a is exclusively expressed by Langerhans cells. However, inflammatory cytokines can induce the expression of CD1a on myeloid cells. In this context, we will investigate the role of CD1a in inflammation beyond the skin, exploring its impact on colitis and the development of colitis-associated cancer. Notably, CD1a antigen presentation mainly leads to activation of IL-17-producing T lymphocytes, which are involved in the promotion of colon cancer. Thus, we propose to study a new pathway in which induced CD1a expression in the gut activates Th17 cells, which in turn facilitate tumor growth. This concept is important since it could lead to CD1a as a novel target for therapy of inflammatory skin diseases, as well as colitis and colitis-associated cancer.

Public Health Relevance

Inflammatory skin diseases like psoriasis affect millions of people in the US. However, therapeutic options are limited and often only treat the symptoms and not the cause of disease. The immune system plays an important role in skin inflammation. In this context, the Langerhans cell is an immune cell in the skin, which is able to potently activate inflammatory T lymphocytes. Langerhans cells exclusively express the antigen- presenting molecule CD1a known to stimulate T cells. However, CD1a is only expressed in humans and is lacking in animal models. Therefore, the in vivo role of CD1a on Langerhans cells is not known. In this proposal, we use human CD1a-transgenic mice to demonstrate the important function of CD1a on Langerhans cells in the generation of skin inflammation. We show that CD1a is critical for disease development in mouse models of contact dermatitis and psoriasis. Moreover, we show that CD1a can be induced upon inflammation, and thus is able to influence inflammatory diseases beyond the skin, such as colitis and colitis-associated cancer. This concept is important since it could lead to CD1a as a novel target for therapy of inflammatory diseases of skin and gut, as well as colon cancer.