T cell differentiation
T cell function
Nedd4-family ubiquitylation networks that regulate T cell activation and effector differentiation.
During pathogen infection, T cells orchestrate the immune response to eliminate the pathogen and prevent collateral damage. To do this, T cells must continually respond to external stimuli and adjust their levels of key regulatory proteins. To accomplish this, T cells can alter protein synthesis or change the rate of protein degradation. ?Tagging? a protein with ubiquitin can initiate protein degradation. This process is activated when an E3 ubiquitin ligase transfers ubiquitin to a target protein. While it is known that E3 ubiquitin ligases regulate protein degradation, few details are known regarding when or how these ligases are activated and how they select target proteins. We use genetically engineered mice to study E3 ligase function in vivo. Additionally, we use biochemical techniques to study protein ubiquitylation and protein fate in vitro.
Currently, our interest centers on a family of catalytic HECT-type E3 ubiquitin ligases, termed the Nedd4-family. The 9 members of this family that exist in mammalian cells evolved from a common yeast progenitor known as RSP5. Additionally, we study a small family of membrane tethered Nedd4-family interacting proteins, Ndfip1 and Ndfip2, that have little relatedness to other proteins in the mammalian genome.
We have shown previously that certain Nedd4-family E3 ubiquitin ligases promote T cell activation, while others inhibit effector differentiation and cytokine production. For example, the prototypic family member Nedd4 is needed for T cells to become fully activated, while another Nedd4-family E3 ligase, Itch, prevents IL-4 production and Th2 differentiation. Furthermore, we have determined that certain Nedd4-family members rely on Ndfip1 and Ndfip2 to function. For example, Itch requires Ndfip1 to ubiquitylate substrates. Supporting this, both Itch-deficient and Ndfip1-/- mice develop TH2-mediated inflammation at mucosal barrier sites such as skin, lung and gut. Our current work is focused on defining how Ndfip proteins promote E3 ligase function in vivo and in vitro.
We are now characterizing other Ndfip/Nedd4 E3 ligase partnerships and probing the biologic consequence of the formation and activation of these ubiquitylation complexes. These studies are likely to reveal new substrates that are ubiquitylated by such complexes.
Understanding the context and consequence of these ubiquitin complexes will allow us to design therapeutic approaches for tuning ubiquitylation in disease settings. Based on our data from mouse models, this approach may be particularly useful to treat inflammation and allergic disease.
Chris Riling-Graduate Student (CBP)
Allison Beal-Postdoctoral Fellow
Vanessa Kurzwiel-Graduate Student (MVP)
Natalia Ramos-Hernandez-Graduate Student (IGG)
Ami Laroche-Research Technician
Claire O'Leary-Graduate Student (CBP)
- Associate Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2013– present)
- Assistant Professor of Pathology and Laboratory Medicine at University of Pennsylvania School of Medicine (2007 – 2013)
- PhD, Pathology, University of North Carolina at Chapel Hill (1998)
- BS, Zoology, North Carolina State University (1989)
- Allison M. Beal, Natalia Ramos-Hernandez, Chris R. Riling, Erin A. Nowelsky and Paula M. Oliver. TGF-ß induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentation. Nature Immunology. Vol 13(1) . 2012 January:77-85.
- Ramon HE, Beal AM, Liu Y, Worthen GS, and Oliver PM. The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines. Journal Immunology. Vol 188(8) . 2012 April:4023-31.
- Vanessa Kurzweil, Amy Tarangelo, Paula M Oliver. Gastrointestinal microbiota do not significantly contribute to T cell activation or GI inflammation in Ndfip1-cKO mice. PLOS-One. Vol 7(4) . 2012 April.
- J Mei,Y Liu,N Dai,K Hudock,S Guttentag,JK Kolls,P Oliver,GS Worthen. CXCR2 and CXCL5 Regulate IL-17/G-CSF axis and Neutrophil Homeostasis. JCI. Vol 122(3) . 2012 March:974-986.
- Ramon, HE, Riling,CR, Bradfield, J, Yang,B, Hakonarson, H, Oliver, PM. Ndfip1 regulates T cell-mediated gastrointestinal inflammation and susceptibility to inflammatory bowel disease. Mucosal Immunology. Vol 4(3) . 2011 May:314-24.
- Yang B, Gay D, MacLeod MKL, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P., Oliver PM. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells.. Nature Immunology. Vol 9(12) . 2008 December:1356-63.
- Gay DL, Ramón H, Oliver PM.. Cbl- and Nedd4-family ubiquitin ligases: balancing tolerance and immunity.. Immunol. Res.. Springer; 2008 October.