Functionally distinct subsets of CD4 helper T cells, including T follicular helper (Tfh) and T helper type 1 (Th1) subsets, critically govern protective immunity via the induction and maturation of humoral immune responses and phagocyte activation, respectively. Proper genetic programming is required for CD4 T cell helper differentiation, function, and memory formation and dysregulated and inefficient CD4 T cell responses have been linked to suboptimal immunity against multiple acute and chronic infections. Current genetic approaches to interrogate CD4 T cell biology have been largely focused on defining transcriptional programming networks, but transcription factor function and gene expression ultimately depend on epigenetic programming, which represents a major knowledge gap in our understanding of CD4 T cell biology. Thus, fundamental questions remain to be addressed regarding the epigenetic genetic mechanisms that determine pathogen-specific effector and memory CD4 T cell differentiation and function.
Ten-eleven-translocation (TET) family proteins demethylate DNA via a step-wise oxidation of 5’ methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Presence of 5hmC correlates with accessible chromatin. Three TET family proteins (TET1, 2 and 3) act either individually or together to regulate gene expression changes in developing thymocytes, B cells and memory CD8 T cells. However, how or whether these enzymes regulate the differentiation and function of effector and memory CD4 T cells has not been investigated.
The central hypothesis for my dissertation studies is that mature, peripheral CD4 T cell differentiation and function is governed by activity of TET proteins.
Vijay R., Guthmiller J.J., Sturtz A.J., Crooks S., Johnson J.T… Butler N.S. Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation. J Exp Med. 2021 Jun 7;218(6):e20202359. doi: 10.1084/jem.20202359.
Honors & Awards
- NIAID F31 Predoctoral Fellowship – AI164640
- Trainee Abstract Award – AAI Immunology2021 May 2021
- NIAID T32 Predoctoral Training Grant – AI007511 2019-2021