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Th9 cells and protective TB immunity

Award Number: R01AI168543
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: 03/09/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Th9 cells and protective TB immunity - -γ-producing Th1 cells have been extensively studied for development of novel vaccines and therapeutics against Mycobacterium tuberculosis (Mtb) infection. However, recent studies demonstrate that Mtb-specific Th1 cells alone do not predict protection against tuberculosis (TB). Therefore, although Th1 cells are required for controlling Mtb replication, other types of immune cells may be needed to prevent infection and eradicate the bacteria. We recently found that a subset of IL-9-producing CD4+ T cells (Th9) can mediate protective immunity against Mtb infection. Th9 cells can be differentiated from naïve CD4+ T cells with TGF-β and IL-4, and play important roles in antitumor immunity and immunity related to allergic reactions. The role of Th9 cells in Mtb infection, however, remain largely unknown. We discovered a role for Th9 cells in TB immunity when we analyzed the transcriptomes in CD4+ T cells from healthy volunteers vaccinated with BCG and from people with latent TB infection (LTBI). IL-9 mRNA in CD4+ T cells topped the list of genes increased after BCG vaccination and LTBI. A significant increase in IL-9 production by bronchoalveolar lavage (BAL) cells after stimulation with infectious Mtb was observed only in LTBI patients and people vaccinated with oral (PO) BCG, indicating induction of Mtb-specific Th9 memory responses. To test whether Th9 cells mediate intracellular Mtb killing, we differentiated Mtb-specific Th9 cells from ESAT6-TCR transgenic mice and co-cultured these Th9 cells with Mtb-infected murine macrophages. Intracellular mycobacterial growth was significantly reduced in macrophages after interacting with Th9 cells. Moreover, neutralizing IL-9 abolished the inhibitory effects of Th9 cells, while addition of recombinant IL-9 alone inhibited intracellular bacterial growth. Furthermore, adoptive transfer of Mtb-specific Th9 cells into syngeneic RAG1/2-/- mice suppresses Mtb growth in vivo. In addition, we found that IL-9 was increased and Mtb growth decreased in mice deficient in MCPIP1, a new RNA-binding protein affecting T cell activation. Deletion of MCPIP1 in Th9 cells resulted in a significantly enhanced IL-9 production upon restimulation. Based on our preliminary findings, we hypothesize that Mtb-specific Th9 cells represent a distinct subset of CD4+ T cells important for protective TB immunity. Strategies inducing Mtb- specific Th9 cells could be used to develop more effective TB vaccines and/or immunotherapies. We propose three aims to test this novel hypothesis: Aim 1 to determine the effects of Mtb-specific Th9 cells on protective TB immunity; Aim 2 to define the roles of IL-9 in vaccine-induced protection against Mtb infection using genetically engineered mice, and Aim 3 to identify the source for IL-9 in PBMC and BAL cells from BCG vaccinated individuals, and the mechanisms of Mtb-specific Th9 cell-mediated bacterial killing in human macrophages. These studies will have a significant impact on improving our understanding of host protective immune mechanisms against Mtb infection, and provide the rationale for targeting Mtb-specific Th9 cells as a new strategy for more effective TB vaccines and/or immunotherapies against Mtb infection.


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: 2026 ( Subtotal = $667,594 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	5	2/19/2026	NON-COMPETING CONTINUATION	$667,594
														Subtotal = $667,594

Issue Date FY: 2025 ( Subtotal = $667,594 )
2025	2025	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	4	4/17/2025	NON-COMPETING CONTINUATION	$667,594
														Subtotal = $667,594

Issue Date FY: 2024 ( Subtotal = $667,594 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$66,759
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	3	2/27/2024	NON-COMPETING CONTINUATION	$600,835
														Subtotal = $667,594

Issue Date FY: 2023 ( Subtotal = $667,594 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	2	2/16/2023	NON-COMPETING CONTINUATION	$667,594
														Subtotal = $667,594

Issue Date FY: 2022 ( Subtotal = $667,594 )
2022	2022	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	1	3/9/2022	NEW	$667,594
														Subtotal = $667,594

Grand Total All Awards = $3,337,970

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Th9 cells and protective TB immunity

Award Number: R01AI168543

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: 03/09/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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