White, Tristan
(2024)
The Role of RNA Binding Proteins HnRNP A1 and HnRNP L in T cells.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
While RNA binding proteins (RBPs) like heterogeneous nuclear ribonucleoproteins (hnRNPs) have recently emerged as regulators of gene expression in immune cells, their effect on T-cell fate needs further investigation. HnRNPs are crucial in many aspects of RNA biogenesis, alternative splicing, expression, and function. We and others have shown that TCR signaling strength through the PI3K/Akt/mTOR pathway can control T cell differentiation. Differences in PI3K/Akt/mTOR signaling affect T cell fate and potentially Akt phosphorylation of hnRNP A1, which depends on TCR signal strength. HnRNP A1 is known to have a single Akt phosphorylation site at S199, and our lab has generated a new mutant mouse model, hnRNP A1-S199A, to study the effect that phosphorylation of the hnRNP A1-S199 has on T cell fate and function. We found that the hnRNP A1-S199A mutation did not affect the immune system at steady state compared to the wild type. We also found no difference in Th1, Th2, Th17, and Treg differentiation in vitro. Using an in vivo oral tolerance model, we saw no difference in Treg induction or Tfh differentiation and function using an NP immunization model. During T cell development, hnRNP L is known to regulate the proliferation and migration of thymic pre-T cells, as loss of hnRNP L in early T cell development results in a failure of T cells to reach the periphery. Little is known about how hnRNP L affects T cell activation and function. Our lab has used CD4Cre × Hnrnplfl/fl (KO) mice model to understand the role of hnRNP L in peripheral T cells. We found that at steady state, KO CD4+ T cell mice have normal migration from the thymus, but there is a reduction in peripheral T cell percentage and numbers. We also show that hnRNP L plays an essential role in Th1, Th2, and Tregs differentiation and T cell survival in vitro. Using two in vivo NP immunization models, we pfound hnRNP L is critical for Tfh differentiation and germinal center formation. This study shows that hnRNP A1 S199 is not a primary site of phosphorylation, and hnRNP L expression is critical for T cell function and survival.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
27 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
2 February 2024 |
| Approval Date: |
27 September 2024 |
| Submission Date: |
26 April 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
110 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
hnRNPA1, HnRNPL, T cells |
| Date Deposited: |
27 Sep 2024 15:31 |
| Last Modified: |
27 Sep 2024 15:31 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46350 |
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