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Eric S Huseby PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentPathology
AddressUniversity of Massachusetts Medical School
55 Lake Avenue North
Worcester MA 01655
Phone508-856-2180
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentPathology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentImmunology and Virology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program


    Collapse Biography 
    Collapse education and training
    University of Washington, Seattle, WA, United StatesBSChemical Engineering
    University of Washington, Seattle, WA, United StatesPHDImmunology

    Collapse Overview 
    Collapse overview

    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.



    Collapse 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.



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




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Stadinski BD, Blevins SJ, Spidale NA, Duke BR, Huseby PG, Stern LJ, Huseby ES. A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3+ Treg cell development. Nat Immunol. 2019 Jun 17. PMID: 31209405.
      View in: PubMed
    2. Rowe JH, Delmonte OM, Keles S, Stadinski BD, Dobbs AK, Henderson LA, Yamazaki Y, Allende LM, Bonilla FA, Gonzalez-Granado LI, Celikbilek Celik S, Guner SN, Kapakli H, Yee C, Pai SY, Huseby ES, Reisli I, Regueiro JR, Notarangelo LD. Patients with CD3G mutations reveal a role for human CD3? in Treg diversity and suppressive function. Blood. 2018 May 24; 131(21):2335-2344. PMID: 29653965.
      View in: PubMed
    3. Blevins S, Huseby ES. Killer T cells with a beta-flavi(r) for dengue. Nat Immunol. 2017 Oct 18; 18(11):1186-1188. PMID: 29044243.
      View in: PubMed
    4. Rowe JH, Stadinski BD, Henderson LA, Ott de Bruin L, Delmonte O, Lee YN, de la Morena MT, Goyal RK, Hayward A, Huang CH, Kanariou M, King A, Kuijpers TW, Soh JY, Neven B, Walter JE, Huseby ES, Notarangelo LD. Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity. J Allergy Clin Immunol. 2017 12; 140(6):1739-1743.e7. PMID: 28864286.
      View in: PubMed
    5. Wyss L, Stadinski BD, King CG, Schallenberg S, McCarthy NI, Lee JY, Kretschmer K, Terracciano LM, Anderson G, Surh CD, Huseby ES, Palmer E. Affinity for self antigen selects Treg cells with distinct functional properties. Nat Immunol. 2016 Sep; 17(9):1093-101. PMID: 27478940.
      View in: PubMed
    6. Stadinski BD, Shekhar K, Gómez-Touriño I, Jung J, Sasaki K, Sewell AK, Peakman M, Chakraborty AK, Huseby ES. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat Immunol. 2016 Aug; 17(8):946-55. PMID: 27348411.
      View in: PubMed
    7. Stadinski BD, Obst R, Huseby ES. A "hotspot" for autoimmune T cells in type 1 diabetes. J Clin Invest. 2016 Jun 1; 126(6):2040-2. PMID: 27183386.
      View in: PubMed
    8. Huseby ES, Kamimura D, Arima Y, Parello CS, Sasaki K, Murakami M. Role of T cell-glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms. Front Cell Neurosci. 2015; 9:295. PMID: 26300731.
      View in: PubMed
    9. Parello CS, Huseby ES. Indoctrinating T cells to attack pathogens through homeschooling. Trends Immunol. 2015 Jun; 36(6):337-43. PMID: 25979654.
      View in: PubMed
    10. Attaf M, Huseby E, Sewell AK. aß T cell receptors as predictors of health and disease. Cell Mol Immunol. 2015 Jul; 12(4):391-9. PMID: 25619506.
      View in: PubMed
    11. Stepanek O, Prabhakar AS, Osswald C, King CG, Bulek A, Naeher D, Beaufils-Hugot M, Abanto ML, Galati V, Hausmann B, Lang R, Cole DK, Huseby ES, Sewell AK, Chakraborty AK, Palmer E. Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell. 2014 Oct 9; 159(2):333-45. PMID: 25284152.
      View in: PubMed
    12. Keck S, Schmaler M, Ganter S, Wyss L, Oberle S, Huseby ES, Zehn D, King CG. Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation. Proc Natl Acad Sci U S A. 2014 Oct 14; 111(41):14852-7. PMID: 25267612.
      View in: PubMed
    13. Stadinski BD, Trenh P, Duke B, Huseby PG, Li G, Stern LJ, Huseby ES. Effect of CDR3 sequences and distal V gene residues in regulating TCR-MHC contacts and ligand specificity. J Immunol. 2014 Jun 15; 192(12):6071-82. PMID: 24813203.
      View in: PubMed
    14. Stadinski BD, Huseby ES. Identifying environmental antigens that activate myelin-specific T cells. Trends Immunol. 2014 Jun; 35(6):231-2. PMID: 24820694.
      View in: PubMed
    15. Sasaki K, Bean A, Shah S, Schutten E, Huseby PG, Peters B, Shen ZT, Vanguri V, Liggitt D, Huseby ES. Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J Immunol. 2014 Apr 1; 192(7):3029-42. PMID: 24591371.
      View in: PubMed
    16. 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. PMID: 23663778.
      View in: PubMed
    17. 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. PMID: 23248307.
      View in: PubMed
    18. Huseby ES, Stadinski BD, Trenh P, Stern LJ. Response to Garcia et al. Immunity. 2012 Jun 29; 36(6):889-90. PMID: 22705102.
      View in: PubMed
    19. 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. PMID: 22566945.
      View in: PubMed
    20. 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. PMID: 22384241.
      View in: PubMed
    21. 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. PMID: 22101158.
      View in: PubMed
    22. 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. PMID: 21683626.
      View in: PubMed
    23. 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. PMID: 20421471.
      View in: PubMed
    24. 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; 2(4):a005140. PMID: 20452950.
      View in: PubMed
    25. 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. PMID: 18946038.
      View in: PubMed
    26. 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. PMID: 18424189.
      View in: PubMed
    27. 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. PMID: 18308592.
      View in: PubMed
    28. 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. PMID: 17920446.
      View in: PubMed
    29. 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. PMID: 17493959.
      View in: PubMed
    30. 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. PMID: 17202350.
      View in: PubMed
    31. 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. PMID: 17041605.
      View in: PubMed
    32. 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. PMID: 16623770.
      View in: PubMed
    33. 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. PMID: 16051149.
      View in: PubMed
    34. 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. PMID: 15853746.
      View in: PubMed
    35. 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. PMID: 15114657.
      View in: PubMed
    36. 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. PMID: 15094798.
      View in: PubMed
    37. 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. PMID: 14504410.
      View in: PubMed
    38. 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. PMID: 12045239.
      View in: PubMed
    39. 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. PMID: 11812409.
      View in: PubMed
    40. Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlén C, Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med. 2001 Sep 3; 194(5):669-76. PMID: 11535634.
      View in: PubMed
    41. Huseby ES, Sather B, Huseby PG, Goverman J. Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity. 2001 Apr; 14(4):471-81. PMID: 11336692.
      View in: PubMed
    42. Bernhard H, Huseby ES, Hand SL, Lohmann M, Batten WY, Disis ML, Gralow JR, Meyer zum Büschenfelde KH, Ohlén C, Cheever MA. Dendritic cells lose ability to present protein antigen after stimulating antigen-specific T cell responses, despite upregulation of MHC class II expression. Immunobiology. 2000 Apr; 201(5):568-82. PMID: 10834314.
      View in: PubMed
    43. Huseby ES, Goverman J. Tolerating the nervous system: a delicate balance. J Exp Med. 2000 Mar 6; 191(5):757-60. PMID: 10704457.
      View in: PubMed
    44. Huseby ES, Ohlén C, Goverman J. Cutting edge: myelin basic protein-specific cytotoxic T cell tolerance is maintained in vivo by a single dominant epitope in H-2k mice. J Immunol. 1999 Aug 1; 163(3):1115-8. PMID: 10415003.
      View in: PubMed
    45. Loftus C, Huseby E, Gopaul P, Beeson C, Goverman J. Highly cross-reactive T cell responses to myelin basic protein epitopes reveal a nonpredictable form of TCR degeneracy. J Immunol. 1999 Jun 1; 162(11):6451-7. PMID: 10352259.
      View in: PubMed
    46. Goverman J, Brabb T, Huseby ES, Farr AG. TCR signaling regulates thymic organization: lessons from TCR-transgenic mice. Immunol Today. 1997 May; 18(5):204-8. PMID: 9153949.
      View in: PubMed
    47. Brabb T, Huseby ES, Morgan TM, Sant'Angelo DB, Kirchner J, Farr AG, Goverman J. Thymic stromal organization is regulated by the specificity of T cell receptor/major histocompatibility complex interactions. Eur J Immunol. 1997 Jan; 27(1):136-46. PMID: 9022010.
      View in: PubMed
    48. Disis ML, Bernhard H, Shiota FM, Hand SL, Gralow JR, Huseby ES, Gillis S, Cheever MA. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood. 1996 Jul 1; 88(1):202-10. PMID: 8704175.
      View in: PubMed
    49. Takahashi M, Chen W, Byrd DR, Disis ML, Huseby ES, Qin H, McCahill L, Nelson H, Shimada H, Okuno K, et al. Antibody to ras proteins in patients with colon cancer. Clin Cancer Res. 1995 Oct; 1(10):1071-7. PMID: 9815896.
      View in: PubMed
    50. Cheever MA, Disis ML, Bernhard H, Gralow JR, Hand SL, Huseby ES, Qin HL, Takahashi M, Chen W. Immunity to oncogenic proteins. Immunol Rev. 1995 Jun; 145:33-59. PMID: 7590829.
      View in: PubMed
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