BBS Faculty Member - Kai Wucherpfennig

Kai Wucherpfennig

Department of Cancer Immunology and AIDS

Dana Farber Cancer Institute
44 Binney Street, Dana Building, Room 1410
Boston MA 02115
Tel: 617-632-3086
Fax: 617-632-2662
Email: kai_wucherpfennig@dfci.harvard.edu
Lab Members: 8 postdoctoral fellows, 4 graduate students, 1 staff scientist
Visit my lab page here.



The work of our group focuses on the molecular mechanisms of T cell activation and the application of these insights to the eradication of cancer cells by T cells.

Molecular mechanisms of T cell receptor recognition and signaling
Many receptors in the immune system signal through cytoplasmic tyrosine-based motifs referred to as ITAMs. In textbooks, these cytoplasmic domains are shown as flexible chains that float in the cytosol which suggested that they are readily accessible to tyrosine kinases. We have discovered that the cytoplasmic domain of one of the T cell receptor (TCR) subunits, the CD3 epsilon chain, is actually membrane-bound in live T cells (1). We determined the NMR structure of the cytoplasmic domain in its lipid-bound state and found that the two critical tyrosines are deeply inserted into the hydrophobic interior of the lipid bilayer. This discovery reveals that receptor activation is controlled by membrane binding of the ITAM and that one of the first steps in signaling has to be the dissociation of the cytoplasmic domain from the membrane. We are now working on the molecular steps that induce dissociation of the ITAM from the membrane, using advanced fluorescence microscopy and biochemical approaches. Also, we are examining the cytoplasmic domains of other receptors important in the immune response. Our hypothesis is that membrane binding is a widely utilized mechanism for the control of receptor activation and that the mechanisms for release from the membrane are highly conserved. We have also studied the mechanisms of T cell receptor assembly and shown that assembly of the TCR with its three signaling dimers occurs primarily within the plasma membrane through highly unusual interactions between basic and acidic residues. Again, this mechanism is conserved across many receptors in the immune system (2, 3). Thus, we are aiming to define general principles for receptors in the immune system, using the TCR as an example.

Mechanisms controlling activation of tumor-specific T cells
Clinical studies have shown that the number and activation state of tumor-infiltrating T cells can predict outcome with a greater accuracy than conventional staging methods. However, T cells are frequently inactivated in the tumor microenvironment. We are working on the signaling and transcriptional mechanisms responsible for inhibition of T cells in tumors, with the goal of reversing this functional block. We are currently performing genome-wide shRNA screens in vivo in order to identify shRNAs that can restore the functional activity of tumor-specific T cells. Such shRNAs may be useful for enhancing the efficacy of adoptive T cell therapies in cancer.



Last Update: 8/22/2013



Publications

Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD, Carman CV, Chou JJ, Wucherpfennig KW. Regulation of T cell receptor activation by dynamic membrane binding of the CD3e cytoplasmic tyrosine-based motif. Cell 2008, 135:702-13.

Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 2002; 111: 967-79.

Call ME, Schnell JR, Xu C, Lutz RA, Chou JJ, Wucherpfennig KW. The structure of the zeta-zeta transmembrane dimer reveals polar features essential for its assembly with the T cell receptor. Cell 2006; 127: 355-68.

Anders AK, Call MJ, Schulze MS, Fowler KD, Schubert DA, Seth NP, Sundberg EJ, Wucherpfennig KW. HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide. Nat Immunol 2011; 12: 54-61.



© 2013 by the President and Fellows of Harvard College