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The Role of Intestinal Epithelial Cells in the Generation of Protective CD4 Cytotoxic T Lymphocytes

Award Number: F31DK124078
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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The Role of Intestinal Epithelial Cells in the Generation of Protective CD4 Cytotoxic T Lymphocytes - PROJECT SUMMARY/ABSTRACT CD4 cytotoxic T lymphocytes (CTL) accumulate in the small intestinal epithelium during steady state, but their development and purpose(s) at this barrier are largely unknown. The unique localization of CD4 CTL to the small intestinal epithelium suggests tissue-specific properties that direct CD4 CTL to develop from naive CD4 T helper (Th) cells. Similar to traditional myeloid antigen-presenting cells, intestinal epithelial cells (IECs) express MHC class II (MHCII), suggesting a possible influence over nearby CD4 T cells. In addition, IECs are constantly processing luminal contents and are expected to present tolerized antigens (e.g. diet or commensal bacteria-derived) to CD4 T cells at its baso-lateral side. I have generated preliminary evidence that MHCII-processing of dietary antigens by IECs is involved in the accumulation of CD4 CTL in the small intestinal epithelium. Building on this finding, I hypothesize that the epithelium has a direct role in regulating CD4 Th cell conversion into CD4 CTL. This resulting CD4 CTL population is further predicted to have a non-redundant protective role against foodborne pathogens. Taken together, the presence of epithelial CD4 CTL could represent an immune strategy that simultaneously adds an arm of defense while providing an alternative form of immunoregulation. The proposed studies are expected to yield novel insights on mucosal CD4 T cell immunology that could be relevant for the prevention or treatment of gastrointestinal diseases as well as improving vaccine development strategies. I propose to use a combination of conditional knock-out mouse models and a Salmonella pathogen model analyzed with state-of-the-art flow cytometry, next-generation sequencing, and high-resolution microscopy to determine the role of IECs as Ag-presenting cells in reprogramming CD4 Th cells into CD4 CTL and the functional roles of these CD4 CTL during steady state or during infection. All experiments will be performed at La Jolla Institute for Immunology, a leader in biomedical science research, under the guidance of sponsor Dr. Hilde Cheroutre and co-sponsor Dr. Mitchell Kronenberg. In addition, I will receive professional guidance and support from my collaborators and thesis committee in performing the studies. My growth as a scientist will also be supplemented with classes and events held through the Biomedical Sciences PhD program at UC San Diego. In summary, the proposed studies and training objectives of this F31 award application are geared towards training me as to become a versatile independent researcher with a specialty in mucosal immunology and strong scientific acumen.


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 = -$1,509 )
2023	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/15/2023	NON-COMPETING CONTINUATION	-$1,509
														Subtotal = -$1,509

Issue Date FY: 2022 ( Subtotal = $13,866 )
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/21/2022	NON-COMPETING CONTINUATION	-$4,521
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/20/2022	NON-COMPETING CONTINUATION	$18,072
2022	2022	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/2/2022	NON-COMPETING CONTINUATION	$315
														Subtotal = $13,866

Issue Date FY: 2021 ( Subtotal = $40,450 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/4/2021	NON-COMPETING CONTINUATION	$40,450
														Subtotal = $40,450

Issue Date FY: 2020 ( Subtotal = $39,934 )
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/25/2020	NEW	$39,934
2020	2020	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/25/2020	NEW	$0
														Subtotal = $39,934

Grand Total All Awards = $92,741

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The Role of Intestinal Epithelial Cells in the Generation of Protective CD4 Cytotoxic T Lymphocytes

Award Number: F31DK124078

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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