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.

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.