William F Hawse, PhD
Campus: 200 Lothrop St
Office: BSTWR E1000-2A
Pittsburgh, PA 15261
- Assistant Professor, Department of Immunology
T cells are mediators of the adaptive immune response. To properly mount a response, T cells use extracellular receptors to sense their environment and transduce signals to intracellular signaling networks. Following ligation of the T cell receptor (TCR) to an antigen, both phospholipid and kinase signaling networks are activated. Our working hypothesis is that T cells encode different signaling inputs by generating different phosphatidylinositols and qualitatively different phosphoproteomes that drive alternate cellular differentiation programs. We utilize a combination of cellular immunology, mass spectrometry, biophysics, high resolution microscopy, high content imaging, chemical genetics and single cell assays to study the mechanisms underlying T cell activation. Below are projects that we are currently pursuing:
1. Molecular mechanisms that encode TCR signal strength
TCR signaling is a dominant factor that controls cell fate decisions and T cell development. We identified that T cells encode TCR signal strength by generating different species of phosphatidylinositols, which are bioactivate and regulate processes including kinase activation at the cell membrane. In turn, generation of different phosphatidylinositols engages different signaling networks, including the AKT kinase, to control CD4+ T cell fate decisions. We are currently exploring how differential phosphatidylinositol synthesis regulates TCR organization at the immunological synapse with antigen presenting cells, how differential phosphatidylinositol synthesis regulates kinase signaling networks and how manipulation of phosphatidylinositol content of the plasma membrane with chemical genetic approaches impacts CD4+ T cell differentiation.
2. Defining mechanisms of cross-talk between TCR and cytokine signaling networks
Most functions of T cells require a TCR signal. Additionally, specific microenvironments across the body contain different levels of cytokines, which also regulate T cells. While the importance of TCR and cytokine signaling for T cells are well appreciated, the cross-talk between these signaling modalities are less understood. We identified specific kinases, phosphatases and lipid signaling molecules that couple TCR and specific cytokine receptors. We are currently using high content imaging, mass spectrometry, high resolution microscopy, single cell assays and genetic approaches to define biochemical definitions for how multiple receptor signals synergize to form coherent signaling outputs. Our ultimate goal is to understand connections between the TCR and cytokine receptor signaling networks and use this basic knowledge to control T cell differentiation and function in the context of disease settings.
3. Determining the proteomic differences that define CD8+ memory T cell recall responses
Memory CD8+ T cells have a transcriptional landscape and proteome that are optimized to generate a more rapid and robust response to secondary infection Compared to naïve T cells. Rewired kinase networks likely contribute to the superior recall response of memory CD8+ T cells. To test this hypothesis, we in collaboration with the laboratory of Dr. Louis D’Cruz at the University of Pittsburgh developed proteomic methods which identified substantial differences in tyrosine kinase signaling networks between naïve and memory CD8+ T cells. In general, this work identified at the biochemical level how signaling pathways are altered to promote CD8+ memory cell formation and rapid responses to and protection from repeat infections. One specific outcome from our initial screen was that JAK2-catalyzed phosphorylation enabled CBP to bind with higher affinity to acetylated histones, indicating a potential epigenetic mechanism that could contribute to rapid initiation of transcriptional programs in memory CD8+ T cells and CBP itself is essential for conventional effector and memory CD8+ T cell formation. Currently we are further studying CBP in the context of memory formation and are also testing the role of other proteins identified in our screen for their contribution to memory formation and recall responses.
Hawse WF*, Cattley RT. “T cells transduce T cell receptor signal strength by generating different phosphatidylinositols.” J Biol Chem. 2019 Jan 28. pii: JBC.RA118.006524. doi: 10.1074/jbc.RA118.006524. PMID: 30692200.
Piccirillo AR, Cattley RT, D'Cruz LM*, Hawse WF*. “Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice.” J Biol Chem. 2019 Feb 15;294(7):2397-2406. doi: 10.1074/jbc.RA118.006977. Epub 2018 Dec 20. PubMed PMID: 30573679.
*= co-corresponding authors.
Luo W, Hawse W, Conter L, Trivedi N, Weisel F, Wikenheiser D, Cattley RT, Shlomchik MJ. “The AKT kinase signaling network is rewired by PTEN to control proximal BCR signaling in germinal center B cells. Nat Immunol. 2019 Jun;20(6):736-746. doi: 10.1038/s41590-019-0376-3. Epub 2019 Apr 22. PubMed PMID: 31011187.
$= Co-first authors