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Eliciting lung-localized CD4 T cell responses against Mycobacterium tuberculosis in preventive and post-exposure settings

Award Number: R01AI134246
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Eliciting lung-localized CD4 T cell responses against Mycobacterium tuberculosis in preventive and post-exposure settings - SUMMARY An effective vaccination strategy is urgently needed to combat the global scourge of tuberculosis (TB). Due to the known importance of CD4 T cells and IFNγ in immunity against TB, current vaccine efforts are focused on boosting bulk IFNγ-producing CD4 T cell numbers (i.e., Th1 cells). These efforts, however, have been only moderately successful in conferring protection against TB in animal models, and a recent human efficacy trial of a novel candidate vaccine failed to confer measurable protection despite significantly boosting a Th1 response. Thus, there is growing concern that TB vaccines that target Th1 cells may not be adequately effective. We, and others, have recently discovered that adoptive transfer of fully differentiated Th1 cells, expressing high levels of the Th1-promoting transcription factor T-bet, provide little or no protection against murine TB, at least in part because they localize poorly to the lung parenchyma, the primary site of infection. In contrast, less-differentiated CD4 T cells, expressing intermediate levels of T-bet and sharing properties with Tfh and central memory T cells, readily home to the M. tuberculosis (Mtb)-infected lung parenchyma and mediate superior protection. Importantly, however, we have also recently shown that Mtb infection itself drives Th1 cells toward terminal differentiation and a non-protective state. This complicates vaccine approaches in regions of the world in which TB is endemic because most individuals who would benefit from immunization have already been exposed to Mtb or are persistently infected. The goal of this proposal is to elucidate the mechanisms that enable protective CD4 T cell populations to enter and be maintained within the lung parenchyma and to evaluate the influence of pre-existing Mtb infection on these parameters during vaccination in both animal models and human clinical trials. In Aim 1, we will determine the factors that govern the localization of CD4 T cells into the parenchyma, with the prime hypothesis that T cell KLRG1 binds N-cadherin on vascular endothelial cells, thus preventing entry. In addition, the role of key cytokines and glycolipid interactions in granuloma-associated high endothelial venules will also be explored. In Aim 2, we will assess whether vaccine-dependent CD103 expression serves to retain protective CD4 T cells within the parenchyma, and if so, whether this is beneficial or detrimental to immunity. Finally, in Aim 3, we will determine the impact of vaccine dose on priming protective, lung-homing CD4 T cell responses and how previous Mtb exposure influences this priming. The access to clinical samples from dose escalation studies of infected individuals provides a unique opportunity to compare human immune profiles to those observed in mice and to translate our murine findings into testable hypotheses for human TB. The proposed experiments will provide a framework for the future design of novel vaccine delivery strategies with the ability to induce and maintain lung- localizing T cells even in TB endemic regions.


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	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	4/23/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $660,785 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	6	8/6/2021	NON-COMPETING CONTINUATION	$660,785
2021	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	11/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $660,785

Issue Date FY: 2020 ( Subtotal = $676,352 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	7/24/2020	NON-COMPETING CONTINUATION	$676,352
														Subtotal = $676,352

Issue Date FY: 2019 ( Subtotal = $574,721 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	007	4	7/24/2019	NON-COMPETING CONTINUATION	$574,721
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	2	4/30/2019	NON-COMPETING CONTINUATION	-$91,209
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	2	12/24/2018	NON-COMPETING CONTINUATION	$0
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	12/6/2018	NON-COMPETING CONTINUATION	-$736,246
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	12/6/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$736,245
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	006	3	4/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$133,796
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	3	12/24/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2019	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	004	1	4/30/2019	NEW	-$42,587
														Subtotal = $574,721

Issue Date FY: 2018 ( Subtotal = $827,455 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	8/1/2018	NON-COMPETING CONTINUATION	$827,455
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	2	8/7/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $827,455

Issue Date FY: 2017 ( Subtotal = $609,293 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	8/22/2017	NEW	$609,293
														Subtotal = $609,293

Grand Total All Awards = $3,348,606

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Eliciting lung-localized CD4 T cell responses against Mycobacterium tuberculosis in preventive and post-exposure settings

Award Number: R01AI134246

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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