The goal of this proposal is to study the role of transcription factor TCF-1 in determining the epigenetic identity of memory CD8+ T cells. Our adaptive immune system has evolved a unique capacity to remember a pathogen through the generation of memory T cells, which protect the host in the event of reinfection. A better understanding of memory T cell differentiation is crucial for developing strategies to limit T cell responses in organ transplantation or enhance T cell responses during chronic infections. Although it is known that the transcription factor TCF-1 is required for memory CD8+ T cell function, the mechanisms through which this protein controls memory T cell fate remain unclear. Recently, we discovered that a mechanism through which TCF-1 controls the development of T cells relates to its unprecedented ability to create the chromatin accessibility landscape of nave T cells. We found that TCF-1 is selectively enriched at genomic regions that become accessible at the earliest stages of development and is required for the accessibility of these regulatory elements. At the single-cell level, TCF-1 can dictate a coordinate opening of chromatin in T cells. Moreover, ectopic TCF-1 can directly erase repressive chromatin marks in non-T cells, generating de novo open chromatin and inducing the expression of T cell genes. While our recent data determined the novel role of TCF-1 on the epigenome during T cell development, our findings also raised another critical question: what is the role of TCF-1 on the epigenetic identity of memory T cells? We hypothesize that TCF-1 in cooperation with transcription factor partners defines the epigenetic landscape of memory T cells. Our new preliminary data further indicate that TCF-1 expression post T cell activation in vitro can lead to gains in chromatin accessibility at pro-memory genes. However, it remains unclear if TCF-1 expression in T cells responding to an infection can create the epigenetic identity of memory T cells. The domains of TCF-1 required for targeting the chromatin and its potential cooperating factors also remain unknown. How TCF-1 dependent changes on the epigenome relate to pro-memory genes needs to be defined. To answer these questions, we will interrogate the effect of TCF-1 and its potential partners on the chromatin state and accessibility of CD8+ T cells in vitro. Using the state-of-the-art tools, we will generate the map of TCF-1 dependent 3D genome organization and define how changes on the epigenome relate to memory genes. We will further translate these findings in vivo exploiting single-cell epigenomic, transcriptomic, and flow cytometry assays. The expected outcome of this proposal is a detailed understanding of the fundamental interaction between TCF-1 and the chromatin in peripheral T cells which can be exploited to devise combination therapies including epigenetic editing to selectively alter T cell fate at will.

Public Health Relevance

Our adaptive immune system has evolved a unique capacity to remember a pathogen through the generation of memory T cells, which protect the host in the event of reinfection. A better understanding of memory T cell differentiation is crucial for developing strategies to limit T cell responses in organ transplantation or enhance T cell responses during chronic infections. The goal of this proposal is to study the role of transcription factor TCF-1 in determining the epigenetic identity of memory CD8+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL145754-01
Application #
9642390
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Klauzinska, Malgorzata
Project Start
2019-01-15
Project End
2023-12-31
Budget Start
2019-01-15
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104