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Graft-versus-Host Disease: Local Maintenance by Tissue Resident Progenitor T cells

Award Number: R01HL143349
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Graft-versus-Host Disease: Local Maintenance by Tissue Resident Progenitor T cells - Abstract Allogeneic hematopoietic stem cell transplantation (alloSCT) can be a curative therapy for hematologic malignancies and inherited and acquired disorders of blood cells. Alloreactive graft T cells mediate the graft-vs- leukemia (GVL) effect and promote hematopoietic engraftment. However, they also attack normal host tissues causing graft-vs-host disease (GVHD). A central goal of alloSCT research has been to discover methods of minimizing and treating established GVHD with relative sparing of GVL and anti-pathogen immunity. This has been a challenge as most GVHD therapies target basic T cell functions. Development of more specific approaches will require a better understanding of GVHD biology. We considered the question of how GVHD is maintained once established. One possibility is that GVHD is sustained by the continuous generation of alloreactive effector T cells (Teff) in secondary lymphoid tissues (SLT), which then traffic to GVHD target tissues via blood. Alternatively, once tissues are seeded with alloreactive T cells, GVHD is maintained locally without significant input from SLT-derived T cells. A challenge to either model is that chronic alloantigen stimulation induces T cell exhaustion. We found through analysis of T cell clones in a CD4+ T cell receptor transgenic (TCR Tg; “TS1” T cells) GVHD model and through parabiosis of mice with GVHD induced by congenic TS1 cells or polyclonal CD4 and CD8 cells, that once established, GVHD is dominantly maintained locally within tissues with only a small ongoing contribution from blood-derived alloreactive T cells. We identified a tissue- resident Tcf7-expressing (protein is TCF-1) progenitor-like T cell subset (Tpro) in all tissues that we believe is critical for intratissue GVHD maintenance. These cells share features with TCF-1+ “progenitor exhausted” (Tpex) CD8+ T cells described in chronic viral infections and in anti-tumor responses. Tpex develop in the setting of sustained antigen stimulation (also the case with GVHD) and are dependent upon the transcription factor TOX, which we found to be upregulated in alloreactive T cells. Taken together, our data support a model wherein GVHD begins as a systemic immune response initiated by alloreactive T cell clones distributed from SLTs, which morphs into a systemic disease that is the sum of locally maintained intratissue T cells responding to continued local antigen exposure. Tissue-resident alloreactive Tpex would be ideal targets for GVHD prevention (by blocking their formation) and treatment (impair Tpex once formed). Achieving these objectives requires a detailed and mechanistic understanding of alloreactive Tpex/Tpro development and of the extrinsic signals and transcription factors that govern their survival, self-renewal, and differentiation into Teff. We will rigorously test the role of Tcf7 and Tcf7+ cells by inducibly deleting Tcf7 from T cells after GVHD is established. We will fate- map Tcf7-expressing cells using Tcf7-ERT2cre transgenic mice and perform genomic analysis on Tpro and their immediate Teff progeny. We will test the role of TOX using TOX-/- T cells and the role of antigen by varying antigen exposure. We will apply these techniques in the TS1 TCR Tg model and a polyclonal GVHD system.


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 = $767,316 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	6	4/8/2026	NON-COMPETING CONTINUATION	$767,316
2026	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	5	2/20/2026	COMPETING CONTINUATION	$0
														Subtotal = $767,316

Issue Date FY: 2025 ( Subtotal = $747,995 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	5	1/20/2025	COMPETING CONTINUATION	$747,995
														Subtotal = $747,995

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	1/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $632,628 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	5/25/2021	NON-COMPETING CONTINUATION	$632,628
														Subtotal = $632,628

Issue Date FY: 2020 ( Subtotal = $651,301 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	3	5/15/2020	NON-COMPETING CONTINUATION	$651,301
														Subtotal = $651,301

Issue Date FY: 2019 ( Subtotal = $655,553 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	2	5/28/2019	NON-COMPETING CONTINUATION	$655,553
														Subtotal = $655,553

Issue Date FY: 2018 ( Subtotal = $568,001 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	8/6/2018	NEW	$568,001
														Subtotal = $568,001

Grand Total All Awards = $4,022,794

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Graft-versus-Host Disease: Local Maintenance by Tissue Resident Progenitor T cells

Award Number: R01HL143349

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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