Pamela L. Schwartzberg, MD, PhD

Chief, Cell Signaling and Immunity Section

The work in our lab focuses on T lymphocyte signaling with an emphasis on pathways that are affected by primary immunodeficiencies and how they regulate normal immune cell development and function. We take a multidisciplinary approach using mouse genetics, cell biology, biochemistry and genomics, coupled with studies of infectious disease and immunization, to examine functions of signaling molecules in T cells, focusing on tyrosine phosphorylation-initiated pathways. Our overall goals are to help understand the pathophysiology of primary immunodeficiencies, but also to provide insight into the normal regulation of immune cell differentiation and responses to infection and immunization. Our studies of mouse models of X-linked Lymphoproliferation Syndrome and roles of the adaptor SAP and SLAM family receptors in the regulation of T: B cell interactions have helped uncover critical pathways required for follicular T helper (Tfh) cell differentiation and germinal center formation, which are essential for long-term humoral immunity (Czar et al PNAS 2001; Cannons et al JEM 2006, Immunity 2010; Qi et al Nature 2008). In turn, our studies of molecules regulating Tfh cells, including the transcription factor TCF1, have led us to the surprising finding that a similar transcriptional circuitry regulates a stem-like CD8 cell population that is essential for maintaining CD8 cell responses in the face of T cell exhaustion (Wu et al Sci Immunol 2016; Yao et al Nat Immunol 2019, 2021). Our studies of our mouse model of Activated PI3 Kinase Delta Syndrome (APDS/PASLI) have highlighted complex regulation of Tfh cells, GC B cells and autoimmunity by the microbiome (Preite et al Nat Immunol 2018). Current work includes: 1) studies of mouse models of APDS/PASLI to provide insight into how PI3K regulates immunity including expression of TCF1 and the maintenance of longterm CD8 cell responses (Cannons et al Cell Rep 2021); 2) targeted CRISPR screens in primary mouse T lymphocytes to uncover how signaling pathways regulate T cell activation, function and differentiation including Tfh cell generation in vivo (Huang et al Nat Comm, in press). These, in turn, have led to novel insight into the regulation of T cell activation, including regulation of integrin activation and adhesion (Johansen et al, in revision) that are required to develop a proper host immune response.

Suggested Penn mentors: Sarah Henrickson, Michela Locci