Defining molecular determinants of resident memory T cell differentiation and persistence
NIAID - National Institute of Allergy and Infectious Diseases
About This Grant
PROJECT SUMMARY CD8+ resident memory T cells (TRM) play a crucial role in the defense against infection and cancer. Following antigenic challenge, TRM develop and surveil non-lymphoid tissues (NLTs) such as the liver and small intestine to provide long-lasting durable immunity. Within these NLTs, TRM progenitors initiate a universal residency program that is dependent upon induction of the homologous transcription factors BLIMP-1 and Hobit (encoded by Zfp683). These transcription factors are essential for TRM development, as they suppress the expression of egress-supporting molecules like S1PR1 to enforce residency. Although BLIMP-1 is expressed in circulating, conventional effector CD8+ T cells, Hobit expression is restricted to resident immune cells in NLTs including TRM. This suggests that Hobit uniquely facilitates TRM adaptation or survival within peripheral tissues. Despite the critical role of Hobit in TRM differentiation, the mechanism by which Hobit is induced is poorly defined. It is well known that cell-extrinsic factors—including IL-15, TGF-β, and retinoic acid—support the TRM fate; however, how these factors regulate Hobit expression remains unknown. Preliminary data demonstrate that several elements within the Zfp683 locus are accessible and bound by transcription factors downstream of these signals including T-bet, STAT5, and RUNX3. Therefore, I hypothesize that cell-extrinsic tissue cues cooperate with cis-regulatory elements in the Zfp683 locus to induce the expression of Hobit to support the TRM fate. In a preliminary experiment, ablation of one of these candidate cis-regulatory elements resulted in significantly reduced Zfp683 mRNA expression level in liver-resident CD8 T cells and led to a competitive disadvantage in generating TRM cells. Besides cell-extrinsic tissue factors, the presence of antigen and inflammation is also known to regulate TRM development. Previous studies using acute infection models such as LCMV Armstrong have demonstrated that TRM cells persist and expand in rechallenge contexts. However, little is known how persistent stimulation contexts such as chronic infection and autoimmunity influence TRM development and maintenance. Since BLIMP- 1 remains highly expressed during chronic infection but not acute infection, I hypothesize that contexts of persistent TRM activation alter the transcriptional requirement for Hobit during TRM development and persistence, since BLIMP-1 and Hobit play semi-redundant roles in TRM differentiation. Furthermore, I will dissect how antigen presence and inflammation differentially impact TRM responses using a novel model of neoantigen expression in the liver. This research proposal seeks to address critical gaps in our understanding of TRM biology by investigating (1) how cis-regulatory elements integrate tissue-specific cues to drive Hobit expression and (2) how chronic stimulation contexts impact the development and maintenance of TRM identity. By better understanding how TRM development is programmed at the molecular level, therapeutic interventions and vaccination strategies relevant to infection, cancer, and autoimmunity may be improved to further alleviate human disease.
Grant Summary
Defining molecular determinants of resident memory T cell differentiation and persistence is a NIAID - National Institute of Allergy and Infectious Diseases grant providing up to $37K for university, nonprofit, healthcare org. Applications are due 2030-03-31 (open). Check eligibility and apply with FindGrants.
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Up to $37K
2030-03-31
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- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
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Defining molecular determinants of resident memory T cell differentiation and persistence: Frequently Asked Questions
Who is eligible for the Defining molecular determinants of resident memory T cell differentiation and persistence?
Defining molecular determinants of resident memory T cell differentiation and persistence is offered by NIAID - National Institute of Allergy and Infectious Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Defining molecular determinants of resident memory T cell differentiation and persistence provide?
Defining molecular determinants of resident memory T cell differentiation and persistence provides up to $37K per award from NIAID - National Institute of Allergy and Infectious Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Defining molecular determinants of resident memory T cell differentiation and persistence deadline?
Applications for Defining molecular determinants of resident memory T cell differentiation and persistence are due 2030-03-31 (open). Because deadlines can change, verify the date with the funder, NIAID - National Institute of Allergy and Infectious Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Defining molecular determinants of resident memory T cell differentiation and persistence?
To apply for Defining molecular determinants of resident memory T cell differentiation and persistence, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIAID - National Institute of Allergy and Infectious Diseases.