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CD1 autoreactive T cells in human inflammatory skin disease

Award Number: R01AR048632
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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CD1 autoreactive T cells in human inflammatory skin disease - PROJECT SUMMARY CD1 autoreactive T cells in human immune mediated skin disease D. Branch Moody, PI Human skin contains over ten billion resident T cells that participate in host defense, barrier function and autoimmune skin disease. For decades, research into T cell autoreactivity has emphasized T cell receptor (TCR) recognition of MHC-peptide complexes. This R01 program proposes basic research into a different mechanism involving TCR contact with human CD1a proteins expressed on Langerhans cells and lipid antigens. Building on prior studies that discovered lipid antigens and showed the molecular basis for their display by CD1a, we recently discovered an unexpected model whereby T cell receptors directly contact CD1a, and certain endogenous lipids bound to CD1a inhibit TCR contact. The new mechanism of negative regulation expands the scope of CD1a function on Langerhans cells and has potentially broad implications for the control of CD1a autoreactive Th22 T cells in human skin. Using collagen matrices and CD1a tetramers to isolate pure CD1a autoreactive T cells, we will determine T cell receptor patterns, effector functions and the identities of antagonist and agonist lipids in disease settings. We will determine the natural functions of lipid blockers by measuring their production in healthy and diseased skin, as well as in Langerhans cells and related cell types. We will determine the therapeutic potential of lipid blockers by synthesizing analogs to optimize their T cell inhibitory properties. Since we now know that contact allergens can function as CD1a presented antigens, we will test a new model of contact hypersensitivity that involves direct recognition of allergens by lipid specific T cells. Further, we will test the ability of CD1a blockers to prevent T cell response in vivo in CD1a transgenic mice and in human skin explants. In contrast to the ~ 5000 MHC I and II allomorphs present in humans, nearly all humans express the same kind of CD1a proteins. This simplified and relatively uniform T cell system suggests that lipid antigens, lipid antagonists and T cell receptor patterns discovered here will be applicable to all people and can therefore be used to develop therapies against autoimmune 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 = $521,426 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	23	6/27/2024	NON-COMPETING CONTINUATION	$521,426
														Subtotal = $521,426

Issue Date FY: 2023 ( Subtotal = $557,303 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	22	7/19/2023	NON-COMPETING CONTINUATION	$557,303
2023	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	21	11/4/2022	COMPETING CONTINUATION	$1
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	11/4/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $557,303

Issue Date FY: 2022 ( Subtotal = $584,768 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	21	6/15/2022	COMPETING CONTINUATION	$584,768
2022	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	6/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $584,768

Issue Date FY: 2021 ( Subtotal = $493,237 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	6/15/2021	NON-COMPETING CONTINUATION	$493,237
														Subtotal = $493,237

Issue Date FY: 2020 ( Subtotal = $508,492 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	6/9/2020	NON-COMPETING CONTINUATION	$508,492
														Subtotal = $508,492

Issue Date FY: 2019 ( Subtotal = $367,037 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	5/1/2019	NON-COMPETING CONTINUATION	$367,037
														Subtotal = $367,037

Issue Date FY: 2018 ( Subtotal = $508,492 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	5/11/2018	NON-COMPETING CONTINUATION	$508,492
														Subtotal = $508,492

Issue Date FY: 2017 ( Subtotal = $527,867 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	16	3/22/2017	COMPETING CONTINUATION	$527,867
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	16	8/22/2017	COMPETING CONTINUATION	$188,607
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	15	11/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$197,276
2017	2016	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	15	8/22/2017	EXTENSION WITH OR WITHOUT FUNDS	-$188,607
2017	2015	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	11/9/2016	NON-COMPETING CONTINUATION	-$197,276
														Subtotal = $527,867

Issue Date FY: 2016 ( Subtotal = $368,420 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	4/25/2016	EXTENSION WITH OR WITHOUT FUNDS	$368,420
														Subtotal = $368,420

Issue Date FY: 2015 ( Subtotal = $368,420 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	4/28/2015	NON-COMPETING CONTINUATION	$368,420
														Subtotal = $368,420

Issue Date FY: 2014 ( Subtotal = $361,051 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	5/12/2014	NON-COMPETING CONTINUATION	$361,051
														Subtotal = $361,051

Issue Date FY: 2013 ( Subtotal = $349,999 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	7/15/2013	NON-COMPETING CONTINUATION	$18,421
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	4/23/2013	NON-COMPETING CONTINUATION	$331,578
														Subtotal = $349,999

Issue Date FY: 2012 ( Subtotal = $368,420 )
2012	2012	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	4/17/2012	COMPETING CONTINUATION	$368,420
														Subtotal = $368,420

Issue Date FY: 2011 ( Subtotal = $350,436 )
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	3/24/2011	NON-COMPETING CONTINUATION	$328,535
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	6/8/2011	NON-COMPETING CONTINUATION	$21,901
														Subtotal = $350,436

Issue Date FY: 2010 ( Subtotal = $365,038 )
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	3/17/2010	NON-COMPETING CONTINUATION	$365,038
														Subtotal = $365,038

Issue Date FY: 2009 ( Subtotal = $368,725 )
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/10/2009	NON-COMPETING CONTINUATION	$331,853
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	4/16/2009	NON-COMPETING CONTINUATION	$36,872
														Subtotal = $368,725

Issue Date FY: 2008 ( Subtotal = $368,725 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	3/28/2008	NON-COMPETING CONTINUATION	$368,725
														Subtotal = $368,725

Issue Date FY: 2007 ( Subtotal = $376,250 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/5/2007	COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2006 ( Subtotal = $301,126 )
2006	2006	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/30/2006	NON-COMPETING CONTINUATION	$301,126
														Subtotal = $301,126

Issue Date FY: 2005 ( Subtotal = $308,373 )
2005	2005	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/3/2005	NON-COMPETING CONTINUATION	$308,373
														Subtotal = $308,373

Grand Total All Awards = $9,378,642

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CD1 autoreactive T cells in human inflammatory skin disease

Award Number: R01AR048632

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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