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Markers and regulation of regulatory CD8+ T cells during influenza-induced lung immunopathology

Award Number: R01AI151139
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/Abstract Influenza (Flu) infection is a leading cause of respiratory disease and associated death in the world. The annual flu epidemics are estimated to result in 3-5 million cases of severe illness and more than 250,000 deaths. A strong effector immunity is desired for viral clearance, it however can lead to immunopathology if not properly controlled. Severe and fatal influenza diseases are accompanied by an aggressive pro-inflammatory response and an insufficient anti-inflammatory immunity. The production of the immunoregulatory cytokine IL- 10 by flu-specific CD8+ T cells is critical in limiting the lung immunopathology during infection, contributing to host survival and recovery. Knowing how to identify these regulatory CD8+ T cells and understanding how they develop and function are essential for learning how to control flu-induced lung immunopathology. This makes our work highly significant. While much is known about the CD4+ regulatory T cells, the molecular signature and mechanisms that regulate the development and function of IL-10+ regulatory CD8+ T cells remain poorly understood, particularly in the context of influenza-induced airway inflammation. We recently generated an IL- 10GFP/Foxp3RFP dual reporter mouse model that enables detection of IL-10 and Foxp3 in live cells, and undertook a screening for the presence of IL-10+ and/or Foxp3+ T cells under normal and pulmonary inflammatory conditions. We found that Foxp3- IL-10+ CD8+ T cells are present in various organs and disease conditions, and are the major contributors to IL-10 production in the airway during influenza infection. These Foxp3- IL-10+ CD8+ T cells exhibit profound immunoregulatory function against pro-inflammatory innate and adaptive immune responses, indicative of a therapeutic potential. There are however no reliable markers for Foxp3- IL-10+ CD8+ regulatory T cells. We hypothesize that molecular signatures and pathways associated with the development and function of IL-10-producing regulatory CD8+ T cells can be exploited to develop therapeutic strategies against influenza-induced lung immunopathology. Our preliminary studies identified a novel surface signature LAG3hiCD25hiBTLAloCD226lo and the critical transcription factor TCF1 in IL-10+ CD8+ T cells during influenza infection. We propose experiments in two Specific Aims to: (1) determine and validate signature surface markers of IL-10-producing regulatory CD8+ T cells; and (2) determine the role of TCF1 in IL-10-producing regulatory CD8+ T cell development and function. This work is highly innovative as we utilize comprehensive biochemical, genetic and genomics approaches with unique transgenic mouse models, and have exciting preliminary data that can be expanded to provide information of surface markers and critical signaling pathways for a better understanding of the development and immunoregulatory function of IL-10-producing CD8+ T cells during Influenza infection. We expect to unravel potential molecular mechanisms through which flu-induced pathogenesis can be better controlled, which may enhance our ability of developing strategies to control virus-induced immunopathology, morbidity and mortality.


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: 2023 ( Subtotal = $371,444 )
2023	2023	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	3	6/15/2023	NON-COMPETING CONTINUATION	$371,444
														Subtotal = $371,444

Issue Date FY: 2022 ( Subtotal = $382,690 )
2022	2022	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$382,690
														Subtotal = $382,690

Issue Date FY: 2021 ( Subtotal = $382,365 )
2021	2021	LOUISIANA STATE UNIVERSITY	202 HIMES HALL	BATON ROUGE	LA	70803	EAST BATON ROUGE	USA	Allergy and Infectious Diseases Research	000	1	6/24/2021	NEW	$382,365
														Subtotal = $382,365

Grand Total All Awards = $1,136,499

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Markers and regulation of regulatory CD8+ T cells during influenza-induced lung immunopathology

Award Number: R01AI151139

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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