In contrast to conventional T cells that recognize peptides on MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. The abundant expression of CD1a hallmarks Langerhans cells in the skin, a subtype of dendritic cell with antigen-presenting functions. CD1a is able to bind and display a broad spectrum of lipid antigens derived from exogenous sources, such as bacteria, or host origin. The complex immune system of the skin is critically involved in responses to extrinsic insults like allergens, as well as in autoimmune diseases, such as psoriasis. However, the in vivo role of CD1a on Langerhans cells remains enigmatic, since CD1a is expressed in humans but lacking in most animal models. Our hypothesis is that CD1a on Langerhans cells is critical to control inflammatory skin diseases. We will support this hypothesis with the following specific aims: 1) Investigate the impact of CD1a on inflammatory skin diseases. To overcome the obstacle of CD1a lacking in normal experimental animals, we propose to use human CD1a-transgenic mice to study the impact of CD1a on skin inflammation. In preliminary data, we show that the lipidic substance urushiol from the plant poison ivy induces severe skin inflammation in a CD1a-dependent fashion. The immune response is driven by CD1a- expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL- 17 and IL-22. Based on these findings, we propose to investigate the in vivo functions of CD1a in models of psoriasis using our CD1a-transgenic system. 2) Elucidate the mechanism of lipid presentation and recognition in skin inflammation. For this purpose, we will analyze antigen specificity (TCR repertoire) of CD1a-restricted T cells. We plan to generate new tools such as CD1a tetramers and novel techniques for lipid loading of CD1a molecules. Further, we will develop new kinetic measurements for binding of lipids to CD1a. Using structural biology, we resolved the crystal structure of the CD1a/urushiol complex. This forms the basis for subsequent structural studies on the ternary complex between TCR and lipids presented by CD1a, and will also help to identify dominant lipid antigens in inflammatory skin diseases. Finally, we aim to translate our findings to the human system and investigate poison ivy responders and patients suffering from psoriasis with regard to their T cell responses mediated by CD1a. To conclude, we propose CD1a as a novel target for future therapeutic strategies against inflammatory skin diseases.

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. In this proposal, we demonstrate the important role of CD1a on Langerhans cells in the generation of skin inflammation. These studies are important since they could lead to CD1a as a novel target for therapy of inflammatory diseases of the skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI136939-01
Application #
9494914
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rothermel, Annette L
Project Start
2018-01-22
Project End
2022-12-31
Budget Start
2018-01-22
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115