Wednesday, January 15, 2025 1/15/2025

T cell responses to CD1-restricted lipids in tuberculosis

Award Number: R01AI049313
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Activation of  T cells is the mainstay of host defense against Mycobacterium tuberculosis (Mtb) infection and tuberculosis disease (TB). For decades,  T cells were thought to recognize solely peptide antigens bound to polymorphic antigen presenting molecules encoded in the MHC locus. However, the discovery that human CD1 proteins present mycobacterial antigens to T cells provides fundamentally new perspectives on the role of T cells in host defense. First, the foundational studies for this R01 proposal showed that CD1 proteins present mycobacterial glycolipids, phospholipids and lipopeptides to  and  T cells. Thus, lipids must now be considered a diverse class of natural antigens for the human immune system. Second, whereas the MHC locus is the most polymorphic of the human genome, the non-polymorphic nature of CD1 genes creates a situation in which T cell responses are not restricted to an individual’s genotype. Such ‘donor-unrestricted T cells’ have simplified patterns of antigen recognition and T cell receptor usage that could be exploited for therapy. Building on substantial published and unpublished data, this human-focused renewal proposal seeks to test a general model of antigen recognition in which T cell receptors (TCRs) bind onto a roof structure in CD1, or shift away from the roof to contact bacterial antigen. Using recently validated human CD1a, CD1b and CD1c tetramers, we will discover new conserved TCRs that are equivalent to NKT TCRs in the CD1d system. We propose to determine the effector functions of newly discovered innate T cell types in humans, focusing on genes that define an innateness gradient and the known effector functions needed to protect the host against Mtb. Finally, we combine newly produced reagents, including tetramers, transfectants and monoclonal antibodies, to use the guinea pig as a tractable model for study of host T cell responses in the lung and over time. These studies contribute to an innovative view that the human T cell system recognizes and responds to lipid antigens.


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 = $464,254 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	24	5/23/2024	NON-COMPETING CONTINUATION	$46,425
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	24	2/27/2024	NON-COMPETING CONTINUATION	$417,829
														Subtotal = $464,254

Issue Date FY: 2023 ( Subtotal = $464,254 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	23	2/24/2023	NON-COMPETING CONTINUATION	$464,254
														Subtotal = $464,254

Issue Date FY: 2022 ( Subtotal = $493,338 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	22	2/11/2022	NON-COMPETING CONTINUATION	$500,453
2022	2020	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	20	6/29/2022	NON-COMPETING CONTINUATION	-$7,115
2022	2019	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	19	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2018	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	004	18	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	17	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $493,338

Issue Date FY: 2021 ( Subtotal = $539,953 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	21	1/5/2021	COMPETING CONTINUATION	$539,953
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	21	3/16/2021	COMPETING CONTINUATION	$0
2021	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	20	9/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $539,953

Issue Date FY: 2020 ( Subtotal = $429,767 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	20	2/11/2020	NON-COMPETING CONTINUATION	$429,767
														Subtotal = $429,767

Issue Date FY: 2019 ( Subtotal = $455,466 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	3/4/2019	NON-COMPETING CONTINUATION	$455,466
														Subtotal = $455,466

Issue Date FY: 2018 ( Subtotal = $429,784 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	18	2/26/2018	NON-COMPETING CONTINUATION	$429,784
														Subtotal = $429,784

Issue Date FY: 2017 ( Subtotal = $425,337 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	17	2/15/2017	NON-COMPETING CONTINUATION	$425,337
														Subtotal = $425,337

Issue Date FY: 2016 ( Subtotal = $440,994 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	16	2/26/2016	COMPETING CONTINUATION	$440,994
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	16	4/29/2016	COMPETING CONTINUATION	$0
														Subtotal = $440,994

Issue Date FY: 2015 ( Subtotal = $446,250 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	2/13/2015	NON-COMPETING CONTINUATION	$446,250
														Subtotal = $446,250

Issue Date FY: 2014 ( Subtotal = $446,250 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	14	3/19/2014	NON-COMPETING CONTINUATION	$446,250
														Subtotal = $446,250

Issue Date FY: 2013 ( Subtotal = $386,340 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	13	5/29/2013	NON-COMPETING CONTINUATION	$16,440
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13	2/1/2013	NON-COMPETING CONTINUATION	$369,900
														Subtotal = $386,340

Issue Date FY: 2012 ( Subtotal = $411,000 )
2012	2012	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	12	2/16/2012	NON-COMPETING CONTINUATION	$411,000
														Subtotal = $411,000

Issue Date FY: 2011 ( Subtotal = $429,969 )
2011	2011	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	11	3/14/2011	COMPETING CONTINUATION	$429,969
														Subtotal = $429,969

Issue Date FY: 2010 ( Subtotal = $412,575 )
2010	2010	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	10	2/26/2010	NON-COMPETING CONTINUATION	$412,575
														Subtotal = $412,575

Issue Date FY: 2009 ( Subtotal = $416,742 )
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	2/12/2009	NON-COMPETING CONTINUATION	$375,067
2009	2009	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	9	7/2/2009	NON-COMPETING CONTINUATION	$41,675
														Subtotal = $416,742

Issue Date FY: 2008 ( Subtotal = $416,742 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	2/29/2008	NON-COMPETING CONTINUATION	$416,742
														Subtotal = $416,742

Issue Date FY: 2007 ( Subtotal = $424,813 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	3/21/2007	NON-COMPETING CONTINUATION	$424,813
														Subtotal = $424,813

Issue Date FY: 2006 ( Subtotal = $437,500 )
2006	2006	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	2/15/2006	COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2005 ( Subtotal = $339,000 )
2005	2005	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Microbiology and Infectious Diseases Research	000	5	2/9/2005	NON-COMPETING CONTINUATION	$339,000
														Subtotal = $339,000

Grand Total All Awards = $10,108,703

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T cell responses to CD1-restricted lipids in tuberculosis

Award Number: R01AI049313

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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