Postdoctoral Position Available

Eric Huseby, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Pathology

Other Affiliation(s):
   Program in Immunology and Virology

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

The major interest of my lab is to decipher how T cells develop tolerance to self proteins and the autoimmune  consequences of when tolerance fails.  The major route of establishing immunological tolerance of self occurs during the development of T cells in the thymus.  If the T cell receptor (TCR) on developing T cells (thymocytes) binds MHC + self peptides in the thymus with high affinity, the thymocyte is signaled to die.  However, if the TCR on the thymocyte binds MHC + self peptides within a range of medium affinity, T cells are signaled to live and enter the mature T cell repertoire. 

Most mature T cells, when activated, are pro-inflammatory in nature.  However, other T cells adopt an anti-inflammatory phenotype and function to turn off immune responses.  The signaling events which instruct whether thymocytes live or die and whether mature T cells are pro-inflammatory or anti-inflammatory originate from how the TCR binds MHC + self peptides during development in the thymus.  To identify how the biophysics of TCR binding MHC + peptides instructs thymocytes, we have measured the binding affinity and kinetics of binding for a series of TCRs binding several MHC + peptide combinations.  Using these TCR - MHC + peptide combinations, we are studying how different biophysical parameters influence the development T cells. 

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 multiple sclerosis, 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. 

Representative Publications

Huseby E.S., F. Crawford, J. White, P. Marrack, and J.W. Kappler. A major role for interface disrupting amino acids in establishing specificity between TCRs and MHC + peptide complexes. Nat Immunol. 2006 Nov;7(11):1191-9

Huseby E.S., J. White, T. Vass, F. Crawford, D. Becker, C. Pinilla, P. Marrack, J.W. Kappler. 2005. How the T cell repertoire becomes peptide and MHC specific. Cell. Jul 29;122(2):247-60.

Crawford F., E. Huseby, J. White, P. Marrack, J.W. Kappler. 2004. Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. Apr;2(4):E90.

Huseby E.S., F. Crawford, J. White, J. Kappler, P. Marrack. 2003. Negative selection imparts peptide specificity to the mature T cell repertoire. Proc Natl Acad Sci U S A. Sep 30;100(20):11565-70.

Ohlen C., M. Kalos, L.E. Cheng, A.C. Shur, D.J. Hong, B.D. Carson, N.C. Kokot, C.G. Lerner, B.D. Sather, E.S. Huseby, P.D. Greenberg. 2002. CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function. J Exp Med. Jun 3;195(11):1407-18.

Huseby E.S., D. Liggitt, T. Brabb, B. Schnabel. C. Öhlén, J. Goverman. 2001. A Pathogenic Role for Myelin-Specific CD8⁺ T cells in a model for Multiple Sclerosis.  J Exp Med. Sep 3;194(5):669-76.

Huseby E.S., B. Sather, P.G. Huseby, J. Goverman. 2001. Age-dependent T cell tolerance and autoimmunity to myelin basic protein. Immunity. Apr;14(4):471-81.

Huseby E.S., J. Goverman. 2000. Tolerating the nervous system: a delicate balance. J Exp Med. Mar 6;191(5):757-60.

Rotations

Potential rotations

1. To examine how TCR affinity and kinetic of binding to 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.

Biography

1992             B.S. Chemical Engineering, University of Washington

2000             Ph.D. Immunology, University of Washington

2001-2006     Postdoctoral Fellow, Laboratory of Drs. John Kappler and Philippa Marrack

                   Department of Immunology, National Jewish Medical Center

Office: S2 122 & 123
Phone: 508-856-2180
E-mail: Eric.Huseby@umassmed.edu
Keywords: Immunology, Autoimmunity, T lymphocytes, Tolerance

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Huseby for additional details.