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Function of CD1a on Langerhans cells in skin inflammation

Award Number: R01AI136939
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/22/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Function of CD1a on Langerhans cells in skin inflammation - Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	11/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $442,500 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	11/24/2021	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2021 ( Subtotal = $442,500 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	12/11/2020	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2020 ( Subtotal = $442,500 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/3/2020	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2019 ( Subtotal = $442,500 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/21/2018	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2018 ( Subtotal = $442,500 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	1/22/2018	NEW	$442,500
														Subtotal = $442,500

Grand Total All Awards = $2,212,500

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Function of CD1a on Langerhans cells in skin inflammation

Award Number: R01AI136939

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/22/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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