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B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota

Award Number: R01AI155887
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota - Project Summary T-cell-dependent (TD) immunoglobulin A (IgA) responses regulate the composition of the gut microbiota. How B-cell-intrinsic MHCII signaling, which is central to the development of TD IgA responses, influences host- microbiota interactions is unknown. MHCII is widely assumed to promote clonal diversity in effector lymphocyte populations, but this has not been tested. Here, we present evidence in support of the argument that B cell- intrinsic MHCII signaling controls GC dynamics, IgA repertoire diversity, and microbiota composition. Additionally, evidence from our experiments also indicate that both B-cell-intrinsic ablation of MHCII and specific MHC genotypes are associated with enhanced bacterial dissemination from the gut. Based on these observations and previous work by Dr. Kubinak, this R01 seeks to address the hypothesis that B-cell-intrinsic MHCII signaling is a diversifying force of selection promoting clonal diversity in IgA plasma cell pools and individuality in microbiota composition. The objective of Specific Aim #1 is to define the B-cell-intrinsic role of MHCII during GC reactions in the gut; specifically focusing on its role in shaping plasma cell repertoire diversity. A 'Confetti' mouse model will be used to visually demonstrate the effect of MHCII ablation on GC B cell clonal diversity in the gut. IgH sequencing will be used to determine the effect of MHCII polymorphisms and MHC heterozygosity on IgA repertoire diversity in the gut. scRNA sequencing will be used to determine how MHCII influences overlap in clonal diversity between mucosal and systemic plasma cell pools. RAG1-/- bone marrow (BM) chimeras will be used to quantify the effect of MHCII on cross-seeding of gut-derived plasma cells into the BM. Reciprocal BM chimeras will be used to determine the necessity/sufficiency of defects in B-cell-intrinsic MHCII in regulating bacterial dissemination from the gut. The objective of Specific Aim #2 is to test that microbiota composition is an MHCII-dependent phenotype. RAG1-/- and RAG1-/-IL7R-/- BM chimeras will be used to determine the role gut peyer's patches play in driving MHCII-mediated IgA selection in the gut. Microbial colonization experiments in germfree GF RAG1-/- BM chimeras will determine the effect of B-cell-intrinsic MHCII on IgA-targeting of commensal bacteria. A RAG1-/- adoptive transfer model will be used to determine if MHCII surface density influences IgA-mediated targeting of commensals and microbiota composition. Finally, a novel germfree MHC congenic model will be used to explicitly define the role IgA plays in driving individuality in microbiota composition. Results from these studies will address the B-cell-intrinsic role of MHCII in regulating mucosal IgA responses, microbiota composition, and host health. This is a critical gap in our knowledge that is highly relevant to human health. IgA deficiency is the most common form of antibody-deficiency in humans, is strongly linked to genetic variation in MHCII genes, and has been shown to result in dysbiosis that is associated with chronic inflammation. Experiments outlined here are the first to address how MHC genotype influences microbiota composition and bacterial leakage from the gut, a potent driver of chronic immune activation.


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 = $403,347 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	4	4/12/2024	NON-COMPETING CONTINUATION	$403,347
														Subtotal = $403,347

Issue Date FY: 2023 ( Subtotal = $404,092 )
2023	2023	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	3	4/4/2023	NON-COMPETING CONTINUATION	$404,092
														Subtotal = $404,092

Issue Date FY: 2022 ( Subtotal = $453,793 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	2	4/26/2022	NON-COMPETING CONTINUATION	$453,793
														Subtotal = $453,793

Issue Date FY: 2021 ( Subtotal = $431,999 )
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	001	1	6/28/2021	NEW	$0
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	1	5/24/2021	NEW	$431,999
														Subtotal = $431,999

Grand Total All Awards = $1,693,231

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B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota

Award Number: R01AI155887

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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