Dan Eaton

Senior Director, Protein Chemistry

POSTDOC MENTOR

• 25
  years at Genentech
• 5
  publications (2010-12)

The immune system requires a delicate balance between being able to protect against invading pathogens and cancers, and preventing autoimmunity. We are interested in studying the molecular mechanisms involved in regulating this balance between protection and self-tolerance. A group of co-stimulatory and co-inhibitory receptors tightly regulate T-cell activation following engagement of the TCR by antigen-specific MHC present on APCs. In the absence of co-stimulation, T cells will undergo clonal deletion or anergy resulting in T-cell tolerance, whereas in the absence of co-inhibitory signals, tolerance is overridden and an autoimmune response results.

Structurally there are two major classes of co-signalling receptors identified so far - those belonging to the Ig superfamily (CD28, CTLA-4, PD-1 and BTLA) and those to the TNF receptor superfamily (OX40, 41BB, CD27, CD30 and HVEM). The co-stimulatory and co-inhibitory receptors of the Ig family mediate their effects by recruiting receptor-associated kinase or phosphatase activity, respectively. We are investigating the co-inhibitory molecule B- and T-lymphocyte attenuator (BTLA) and the mechanism by which BTLA attenuates lymphocyte activation and proliferation. The activating ligand for BTLA is TNF receptor, herpesvirus entry mediator (HVEM), which engages BTLA to attenuate both T- and B-cell activation. This interaction is the first example of cross talk between an immunoglobulin superfamily (IgSF) and a TNFR family member. BTLA co-inhibitory signaling is complicated by the fact that HVEM also binds to the TNF family member LIGHT, resulting in a co-stimulatory signal for T and B cells. This suggests that HVEM may participate in both activation and attenuation of T- and B-lymphocytes, but the dynamics of the BTLA-HVEM-LIGHT interaction and subsequent signaling is unknown.

To understand how the interactions between BTLA, HVEM, and LIGHT affect immune cell regulation, we developed techniques to determine how these proteins interact and elucidate the physiological relevance of these protein-protein interactions. We use structural and biophysical methods to determine the dynamics between the BTLA-HVEM and HVEM-LIGHT interactions, and evaluate the stoichiometry of the different molecular complexes. In addition, we also employ FRET-based techniques to evaluate the interaction of this complex at the cellular level. Using cellular, molecular, and biochemical methods, we are delineating the BTLA signaling pathway, and how activation of BTLA attenuates positive signaling pathways in T and B cells.

• My Focus

• Publications

  • Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering

    Proceedings of the National Academy of Sciences, 2012, ISSN: 0027-8424

    Grogan, Jane L.; Eaton, Dan L.; Bazan, J. Fernando; Wiesmann, Christian; Comps-Agrar, Laëtitia; Yin, Jianping; Rouge, Lionel; Yu, Xin; Harden-Bowles, Kristin; Stengel, Katharina F.

     View on PubMed

  • A secreted protein microarray platform for extracellular protein interaction discovery.

    Analytical Biochemistry, 21 Sep 2011, ISSN: 1096-0309.

    Ramani, Sree R; Tom, Irene; Lewin, Koh Nicholas; Wranik, Bernd; Depalatis, Laura; Zhang, Jianjun; Eaton, Dan; Gonzalez, Lino C

     View on PubMed

  • Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin's lymphoma.

    Blood, 2009, ISSN: 1528-0020

    Dornan, D.; Bennett, F.; Chen, Y.; Dennis, M.; Eaton D.; Elkins, K.; French, D.; Go, M.A.T.; Jack, A.; Junutula, J.R.; Koeppen, H.; Lau, J.; McBride, J.; Rawstron, A.; Shi, X.; Yu, N.; Yu, S.-F.; Yue, P.; Zheng, B.; Ebens, A.; Polson, A.G.

  • Antibody-drug conjugates for the treatment of Non-Hodgkin's Lymphoma: target and linker-drug selection.

    Cancer Research, 2009, ISSN: 1538-7445

    Polson, A.G.; Calemine-Fenaux, J.; Chan, P.; Chang. W.; Christensen, E.; Clark, S.; de Sauvage, F.J.; Eaton, D.; Elkins, K.; Elliott, M.; Frantz, G.; Fuji, R.N.; Gray, A.; Harden, K.; Ingle, G.S.; Kljavin, N.M.; Koeppen, H.; Nelson, C.; Prabhu, S.; Raab, H.; Ross, S.; Stephan, J.-P.; Scales, S.J.; Spencer, S.D.; Vandlen, R.; Wranik, B.; Yu, S.-F.; Zheng, B.; Ebens, A.

  • The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells.

    Nature Immunology, 2009, ISSN: 1529-2916

    Yu, X.; Harden, K.; Gonzalez, L.C.; Francesco, M.; Chiang, E.; Irving, B.; Tom, I.; Ivelja, S.; Refino, C.J.; Clark, H.; Eaton, D.; Grogan, J.L.

• Education
  • Biochemistry University of Kansas, Ph.D. – 1983
  • Physiology SF State, M.S. – 1980
  • Biology Humboldt State, B.S. – 1978