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The Role of BHLHE40 in Orchestrating Mucosal CD8 T Cell Responses in the Sarcoidosis Lung

Award Number: R01HL179285
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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The Role of BHLHE40 in Orchestrating Mucosal CD8 T Cell Responses in the Sarcoidosis Lung - PROJECT SUMMARY ABSTRACT Sarcoidosis is an interstitial lung disease (ILD) characterized by granulomatous inflammation. Patient mortality from this condition results from progression to pulmonary fibrosis; however, the mechanisms remain unclear. Critically, because the etiology of sarcoidosis is unknown, investigating the mechanisms underlying its pathogenesis in vivo presents a challenge. There is also a lack of consensus within the sarcoidosis research community regarding whether this is primarily a chronic inflammatory or autoimmune disease. Current research has mainly focused on active and acute disease subtypes, with limited studies investigating fibrosis. Moreover, the potential contribution of CD8 T cells has been neglected. Together, these issues represent knowledge gaps in the field of sarcoidosis. In our published studies, we recently demonstrated a critical role for CD8 T cells in fibrotic sarcoidosis, and identified a CD8 T cell subpopulation that exhibits protective effects in the lungs of mice with a mild form of sarcoidosis-like disease (i.e., fewer and smaller granulomas) but acquires a pathogenic phenotype in mice with larger granulomas. These findings suggest that this mouse strain is a tractable preclinical model to investigate both fibrosis-promoting and -suppressing mechanisms in sarcoidosis. Our preliminary analysis has further identified the human equivalent of this subpopulation as CD8 intraepithelial T lymphocytes (IELs). CD8 IELs reside within epithelial barriers but can be readily identified in tissue digests as they uniquely express the CD8 homolog CD8αα. Despite numerous prior studies investigating CD8 IELs in the gut, skin, and splenic epithelia, little is known about these cells at the lung epithelium. Critically, our transcriptomic and flow cytometric analyses of human lung tissue digests implicate CD8 IELs in sarcoidosis pathogenesis. These analyses reveal that in sarcoidosis, maturation markers for CD8 IELs are reduced, whereas a gene network that inhibits CD8 IEL maturation is enriched. Here, to test our overarching hypothesis that pathogenic MHC class II- restricted CD8 IELs drive pulmonary fibrosis in sarcoidosis through their immune-modulatory actions, we propose a comprehensive investigation into the role of CD8 IELs in sarcoidosis using human airway brushings, transgenic mouse models, and a 3D co-culture system with human T cells and bronchial organoids. We further note that despite their localization at the airway epithelium, CD8 IELs can initiate and modulate innate and adaptive immune responses. We intend to achieve these objectives by pursuing the following specific aims: Aim 1. Determine the molecular pathways that regulate the T cell origin and maturation of CD8 IELs; Aim 2. Investigate the tissue residency of antigen-specific CD8 IELs and evaluate their responses to fibrosis; Aim 3. Determine the gene signature and TCR repertoire of CD8 IELs in pulmonary sarcoidosis. In total, the results of our studies are expected to reveal a novel CD8 T cell–driven mechanism that controls the progression of sarcoidosis to pulmonary fibrosis, with potential therapeutic implications.


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 = $808,290 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Lung Diseases Research	000	1	7/7/2026	NEW	$808,290
														Subtotal = $808,290

Grand Total All Awards = $808,290

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The Role of BHLHE40 in Orchestrating Mucosal CD8 T Cell Responses in the Sarcoidosis Lung

Award Number: R01HL179285

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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