Tuesday, March 10, 2026 3/10/2026

Origin and Function of Double Negative T cells in Lupus

Award Number: R01AI150664
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: 11/19/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Origin and Function of Double Negative T cells in Lupus - SUMMARY. Loss of B cell tolerance and production of auto-antibodies (Ab) by plasma cells (PCs) play a major role in Systemic Lupus Erythematosus (SLE) pathology. Though Ab-dependent pathogenesis can be partially controlled with immunosuppression, there is no cure for Ab-mediated disorders. One of the main limitations when developing therapeutic strategies aimed to prevent Ab-dependent pathology is the lack of a precise understanding of how auto-reactive PCs are generated and maintained. In this regard, T follicular helper (Tfh) cells, a subset of CD4+ T cells that provides help to B cells, play a critical role in promoting auto-reactive PCs. As such, the expansion of self-reactive Tfh cells correlates with auto-Ab production and disease severity in murine and human lupus. Similar to Tfh cells, Double-negative (DN) T cells, a particular population of T cells that characteristically lack CD4 and CD8 expression, are also expanded in lupus. Importantly, the frequency of DN T cells also correlates with disease activity and auto-Ab production. Thus, it is generally believed that these cells play a role in autoimmune disease pathogenesis. Despite their putative role in disease development, we do not know what signals control DN T cell formation, and their exact origin and pathogenic function remain largely elusive. Furthermore, the mechanisms that regulate DN T cell homeostasis are entirely unknown, and there are currently no therapies to selectively deplete DN T cells in vivo. The main goal of this proposal is to define the cellular and molecular mechanisms that control pathogenic DN T cell development and function. In this regard, our preliminary data demonstrate that DN T cells and Tfh cells share phenotypic, transcriptional, and developmental requirements. As such, we have identified a population of Bcl6+ DN T cells that phenotypically resemble Tfh cells. The central hypothesis that will be tested in this proposal is that Tfh cells are the precursors of Bcl6+ DN T cells and that, similar to Tfh cells, these cells are efficient B cell helpers. Importantly, our preliminary data also suggest that Bcl6+ DN T cells are more plastic than Tfh cells, which allows them to acquire a “hybrid” Tfh/Th17 signature that we believe is critical for supporting auto-reactive PC responses. In Aim 1, we will test the hypothesis that Tfh cells are precursors of Bcl6+ DN T cells and examine the capacity of these cells to help self-reactive B cell responses. In Aim 2.1, we will test the hypothesis that IL- 17 production by DN T cells is critical for supporting PC responses and Ab-mediated pathology. In Aim 2.2, we will determine the molecular mechanisms controlling the acquisition of a “hybrid” Tfh/Th17 signature. Finally, in Aim 3, we will develop a new synergistic IL-2-based immunotherapy aimed to selectively target Tfh and prevent the differentiation of IL-17+Bcl6+DN T cells by combining “ultra-low” doses of rIL-2 with STAT3- signaling blockade. We believe that our studies will provide a new paradigm for how pathogenic DN T cells are generated, will reveal new pathways implicated in autoimmune disease pathogenesis, and will be crucial for designing new therapeutic interventions to target Tfh and DN T cells and prevent Ab-mediated pathology.


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 = -$378 )
2026	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	3/4/2026	NON-COMPETING CONTINUATION	-$378
														Subtotal = -$378

Issue Date FY: 2025 ( Subtotal = $493,762 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	10/31/2024	NON-COMPETING CONTINUATION	$493,762
														Subtotal = $493,762

Issue Date FY: 2024 ( Subtotal = $509,033 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	4	5/15/2024	NON-COMPETING CONTINUATION	$50,903
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	002	4	9/10/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	10/25/2023	NON-COMPETING CONTINUATION	$458,130
														Subtotal = $509,033

Issue Date FY: 2023 ( Subtotal = $509,033 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	10/28/2022	NON-COMPETING CONTINUATION	$509,033
														Subtotal = $509,033

Issue Date FY: 2022 ( Subtotal = $509,033 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	10/20/2021	NON-COMPETING CONTINUATION	$509,033
														Subtotal = $509,033

Issue Date FY: 2021 ( Subtotal = $398,328 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	1	6/16/2021	NEW	$74,920
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	11/18/2020	NEW	$323,408
														Subtotal = $398,328

Grand Total All Awards = $2,418,812

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Origin and Function of Double Negative T cells in Lupus

Award Number: R01AI150664

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: 11/19/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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