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Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions

Award Number: R01AI143661
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: 09/19/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions - ABSTRACT Most T and B cells exhibit mono-allelic expression (allelic exclusion) of antigen receptor (AgR) genes. Although allelic exclusion was discovered in 1965, its underlying mechanisms and role(s) remain elusive. The initial and prevailing model for allelic exclusion is that expression of one type (specificity) of AgR inhibits autoimmunity by ensuring negative selection of cells with a self-reactive AgR. Consistent with this view, the expression of a second non-autoreactive AgR enables cells expressing a transgenic autoreactive AgR to evade negative selection. Yet, there remains a knowledge gap regarding effects of bi-allelic expression of endogenous TCRb, IgH, or Igk genes whose stringent allelic exclusion is achieved by mono-allelic initiation and feedback inhibition of V recombination. In addition to the likely benefit of mono-allelic expression, the applicant theorizes that mono-allelic AgR assembly suppresses oncogenic translocations from RAG endonuclease-generated DNA double strand breaks (DSBs). An obstacle to elucidating roles of allelic exclusion is the lack of a proven mechanism for mono-allelic initiation of V recombination. This has precluded experimental approaches to increase bi-allelic assembly and expression of AgR loci without otherwise altering V(D)J recombination, DSB responses, and/or lymphocyte development. Recombination signal sequences (RSSs) mediate V(D)J recombination by directing RAG activity. The applicant shows mice harboring replacement of Vb RSSs with a stronger RSS have substantially increased development of T cells with bi-allelic TCRb expression due to increased bi-allelic Vb recombination. Based on his preliminary data, the applicant hypothesizes that weak Vb and VH RSSs limit V recombination to restrict the incidence of V rearrangements on both alleles before feedback inhibition halts further V recombination. He hypothesizes that this stochastic mechanism of lowering V recombination frequency can be exploited to test roles of mono-allelic assembly and expression of TCRb, and possibly IgH, in immune homeostasis. He proposes two complementary but independent aims to test key aspects of these hypotheses. In Aim 1, the PI will use complementary in vitro biochemical and in vivo molecular assays to determine unequivocally whether inherently weak Vb and VH RSSs limit V recombination to enforce mono-allelic initiation of V recombination. In Aim 2, he will use Vb and VH RSS replacement mice to determine the impact of increasing bi-allelic assembly and expression of TCRb or IgH on negative selection of self-reactive cells, predisposition to autoimmunity, and genesis of oncogenic translocations. This project will show how RSSs control mono-allelic assembly and expression of TCRb, and identify if the same stochastic mechanism enforces IgH allelic exclusion. The data will, for the first time, demonstrate a mechanism for mono-allelic initiation of V recombination. The study has great potential to provide definitive evidence for a fundamental tenet of immunology proposed in 1965, but that remains unproven today. The work also may reveal an additional important benefit of mono-allelic initiation of V rearrangements in suppressing lymphoma.


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 = $0 )
2026	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $440,000 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	6/22/2023	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2022 ( Subtotal = $440,000 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	8/16/2022	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2021 ( Subtotal = $440,000 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	8/10/2021	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2020 ( Subtotal = $440,000 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	8/6/2020	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2019 ( Subtotal = $440,000 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	9/19/2019	NEW	$440,000
														Subtotal = $440,000

Grand Total All Awards = $2,200,000

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Elucidating Lymphocyte Allelic Exclusion Mechanisms and Functions

Award Number: R01AI143661

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: 09/19/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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