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    Eric S Huseby PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentPathology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-2180
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

        Overview 
        Narrative

        Biography

        Eric S. Huseby received his B.S. in Chemical Engineering (1992) and Ph.D. in Immunology (2000) from the University of Washington. He was a Howard Hughes Medical Institute post doctoral fellow at the National Jewish Medical Center. He joined the Department of Pathology at the University of Massachusetts as a faculty member in September of 2006 and is a 2007 Arnold and Mabel Beckman Young Investigator and a 2008 Searle Scholar.

        Development of T cell tolerance of self and the autoimmune consequence of when it fails.

        Dr. Eric Huseby

        My lab is focused on the molecular and cellular pathways that govern the generation, maintenance and function of a self tolerant T cell repertoire and the autoimmune consequences of when self tolerance fails. To understand how T cell repertoires develop and how defects in the process lead to autoimmune disease, we are studying three major aspects of T cell function.

        1) How does the specificity of the TCR for MHC + peptides (pMHC) effect T cell development and drive T cell function?

        The ability of T cells to distinguish highly similar peptide ligands bound to a specific class of MHC proteins (pMHC) is the underlying basis for a functioning adaptive immune system. Failures in purging self-reactive TCRs underlie the predisposition to autoimmune disease. To understand why self-reactive T cells are generated and how they recognize pMHC ligands, we have created a series of analytic methods to probe TCR-pMHC binding. The methods we are generating use high-throughput pMHC display libraries to decipher how T cells interact with their pMHC ligands. These novel display libraries will be used to decipher how positive and negative selection shapes the T cell repertoire and to evaluate how TCR cross-reactivity for pMHC ligands influences which T cells enter an immune response.

        2) How does the affinity and binding kinetics of TCR – pMHC interactions impact mature T cell activation and memory T cell formation?

        Mature T cells undergo rapid differentiation into effector and memory T cells when challenged with high affinity pathogen derived ligands. To study how mature T cells discriminate between different affinity ligands, we have created a series of viruses that express biophysically defined T cell ligands for CD4 T cells. Using these recombinant viruses and corresponding CD4 T cells, we are determining when, where and how T cells determine to enter into the immune response.

        3) Why do some self-reactive T cells escape tolerance induction and when activated, induce autoimmunity?

        Although thymic deletion purges most T cells with reactivity for self proteins, autoimmune diseases clearly demonstrate that T cell tolerance of self is incomplete. Many studies have indicated that everyone harbors T cells reactive to self proteins, however only a fraction of people succumb to autoimmune disease. Thus not all self reactive T cell repertoires are pathogenic. Using a T cell mediated model of the autoimmune disease, we are determining whether there is a T cell intrinsic difference in self-reactive, pathogenic versus non-pathogenic T cell repertoires or whether all self reactive T cell repertoires have the capability to pathogenic and autoimmunity is predominately a reaction to a specific triggering event.



        Rotation Projects

        Rotations

        Potential rotations

        1. To examine how TCR affinity and specificity for MHC + peptide influences the development and activation of CD4 T cells.

        2. To assess the impact of self tolerance on the specificity, affinity and pathogenic potential of T cells reactive to proteins expressed in the central nervous system and b-islet cells of the pancreas.



        Post Docs
        A postdoctoral position is available
        to study in this laboratory.
        Clickhereto apply.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Tubo NJ, Pagán AJ, Taylor JJ, Nelson RW, Linehan JL, Ertelt JM, Huseby ES, Way SS, Jenkins MK. Single Naive CD4(+) T Cells from a Diverse Repertoire Produce Different Effector Cell Types during Infection. Cell. 2013 May 9; 153(4):785-96.
          View in: PubMed
        2. Vanguri V, Govern CC, Smith R, Huseby ES. Viral antigen density and confinement time regulate the reactivity pattern of CD4 T-cell responses to vaccinia virus infection. Proc Natl Acad Sci U S A. 2013 Jan 2; 110(1):288-93.
          View in: PubMed
        3. Huseby ES, Huseby PG, Shah S, Smith R, Stadinski BD. Pathogenic CD8 T cells in multiple sclerosis and its experimental models. Front Immunol. 2012; 3:64.
          View in: PubMed
        4. Hsu CJ, Hsieh WT, Waldman A, Clarke F, Huseby ES, Burkhardt JK, Baumgart T. Ligand mobility modulates immunological synapse formation and T cell activation. PLoS One. 2012; 7(2):e32398.
          View in: PubMed
        5. Stadinski BD, Trenh P, Smith RL, Bautista B, Huseby PG, Li G, Stern LJ, Huseby ES. A role for differential variable gene pairing in creating T cell receptors specific for unique major histocompatibility ligands. Immunity. 2011 Nov 23; 35(5):694-704.
          View in: PubMed
        6. Yin L, Huseby E, Scott-Browne J, Rubtsova K, Pinilla C, Crawford F, Marrack P, Dai S, Kappler JW. A Single T Cell Receptor Bound to Major Histocompatibility Complex Class I and Class II Glycoproteins Reveals Switchable TCR Conformers. Immunity. 2011 Jul 22; 35(1):23-33.
          View in: PubMed
        7. Govern CC, Paczosa MK, Chakraborty AK, Huseby ES. Fast on-rates allow short dwell time ligands to activate T cells. Proc Natl Acad Sci U S A. 2010 May 11; 107(19):8724-9.
          View in: PubMed
        8. Wucherpfennig KW, Gagnon E, Call MJ, Huseby ES, Call ME. Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb Perspect Biol. 2010 Apr 1; 2(4):a005140.
          View in: PubMed
        9. Kosmrlj A, Jha AK, Huseby ES, Kardar M, Chakraborty AK. How the thymus designs antigen-specific and self-tolerant T cell receptor sequences. Proc Natl Acad Sci U S A. 2008 Oct 28; 105(43):16671-6.
          View in: PubMed
        10. Teague RM, Greenberg PD, Fowler C, Huang MZ, Tan X, Morimoto J, Dossett ML, Huseby ES, Ohlén C. Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor. Immunity. 2008 May; 28(5):662-74.
          View in: PubMed
        11. Dai S, Huseby ES, Rubtsova K, Scott-Browne J, Crawford F, Macdonald WA, Marrack P, Kappler JW. Crossreactive T Cells spotlight the germline rules for alphabeta T cell-receptor interactions with MHC molecules. Immunity. 2008 Mar; 28(3):324-34.
          View in: PubMed
        12. Huseby ES, Kappler JW, Marrack P. Thymic selection stifles TCR reactivity with the main chain structure of MHC and forces interactions with the peptide side chains. Mol Immunol. 2008 Feb; 45(3):599-606.
          View in: PubMed
        13. Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, Aono H, Ishihara K, Huseby E, Betz UA, Murakami M, Hirano T. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol. 2007 Jun; 19(6):695-702.
          View in: PubMed
        14. Cabbage SE, Huseby ES, Sather BD, Brabb T, Liggitt D, Goverman J. Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance. J Immunol. 2007 Jan 15; 178(2):887-96.
          View in: PubMed
        15. Huseby ES, Crawford F, White J, Marrack P, Kappler JW. Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nat Immunol. 2006 Nov; 7(11):1191-9.
          View in: PubMed
        16. Crawford F, Jordan KR, Stadinski B, Wang Y, Huseby E, Marrack P, Slansky JE, Kappler JW. Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands. Immunol Rev. 2006 Apr; 210:156-70.
          View in: PubMed
        17. Huseby ES, White J, Crawford F, Vass T, Becker D, Pinilla C, Marrack P, Kappler JW. How the T cell repertoire becomes peptide and MHC specific. Cell. 2005 Jul 29; 122(2):247-60.
          View in: PubMed
        18. Goverman J, Perchellet A, Huseby ES. The role of CD8(+) T cells in multiple sclerosis and its animal models. Curr Drug Targets Inflamm Allergy. 2005 Apr; 4(2):239-45.
          View in: PubMed
        19. Huseby E, Kappler J, Marrack P. TCR-MHC/peptide interactions: kissing-cousins or a shotgun wedding? Eur J Immunol. 2004 May; 34(5):1243-50.
          View in: PubMed
        20. Crawford F, Huseby E, White J, Marrack P, Kappler JW. Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. 2004 Apr; 2(4):E90.
          View in: PubMed
        21. Huseby ES, Crawford F, White J, Kappler J, Marrack P. Negative selection imparts peptide specificity to the mature T cell repertoire. Proc Natl Acad Sci U S A. 2003 Sep 30; 100(20):11565-70.
          View in: PubMed
        22. Ohlén C, Kalos M, Cheng LE, Shur AC, Hong DJ, Carson BD, Kokot NC, Lerner CG, Sather BD, Huseby ES, Greenberg PD. CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function. J Exp Med. 2002 Jun 3; 195(11):1407-18.
          View in: PubMed
        23. Wagner TE, Huseby ES, Huseby JS. Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn's disease after treatment with a tumor necrosis factor-alpha inhibitor. Am J Med. 2002 Jan; 112(1):67-9.
          View in: PubMed
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