Tuesday, April 23, 2024
4/23/2024
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 naïve 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
