Assistant Professor

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Address: 1501 N. Campbell Ave.
PO Box 245044
Tucson, AZ 85724-5044
Phone: 520-626-1044
E-Mail: lybarger@email.arizona.edu

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Research Interests

The research interests of the lab center on the biology of MHC class I molecules, which play a central role in immune responses against both intracellular pathogens and tumors.  Within the endoplasmic reticulum (ER), class I molecules bind peptides that are derived from the degradation of endogenously synthesized proteins.  If cells are infected by a virus, for example, class I molecules may also bind unique virus-encoded peptides.  The assembly of class I molecules requires the concerted activity of several accessory molecules in the ER, which are collectively referred to as the peptide-loading complex.    Once peptides bind to class I heavy chains, the complexes are transported to the cell surface where the peptides are accessible for scanning by CD8+ T cells.  If CD8 T cells detect the presence of a foreign (non-self) peptide amid the pool of peptides on class I, the T cells can mount the appropriate response against those cells that display the foreign peptide.  Within this framework, there are two major efforts in the lab:

1) The first concerns virus-encoded molecules that inhibit MHC class I-restricted antigen presentation.  These are employed by viruses to evade the host immune response.  I particular, we study a family of related molecules that all possess ubiquitin ligase activity that is required for class I modulation.  In the case of the mK3 protein of g-herpesvirus 68, class I molecules are degraded rapidly following synthesis in the ER.  Our studies have revealed that mK3 requires class I-dedicated ER accessory molecules (peptide-loading complex) in order to degrade class I heavy chains.  We continue to explore the molecular interactions that are required for mK3 substrate recognition and function.  In addition, this system is being used as an entry point to understand ER degradation pathways under normal conditions.

2) The second project centers on the characterization and applications of single-chain versions of class I.  We, in collaboration with the lab of Ted Hansen, have developed a unique approach for the generation of class I molecules that display uniform, high levels of single antigenic peptides.  These molecules are formed by linking together all three components of a class I molecule (peptide, light chain, and heavy chain) in a single polypeptide.  This technology appears to be widely applicable, since we have applied it successfully to several class I/peptide combinations.  The ability to engineer class I to present high levels of a single peptide has many potential applications.  Currently, we are investigating various applications, such as:  i) Expression following DNA vaccination to prime CD8+ T cell responses against tumors and viruses.  ii) Tetramer production with recombinant forms of these molecules to enumerate antigen-specific T cells.  iii) Transgenic expression in mice to study CD8+ T cell selection and biology on a single peptide/MHC class I background.

Selected Publications

Wang B, Primeau TM, Myers N, Rohrs HW, Gross ML, Lybarger L, Hansen TH, Connolly JM. Nov 2009. A single peptide-MHC complex positively selects a diverse and specific CD8 T cell repertoire. Science, 326:871-4

Jabbour M, Campbell EM, Fares H, Lybarger L. Nov 2009. Discrete domains of MARCH1 mediate its localization, functional interactions, and posttranscriptional control of expression. J Immunol, 183:6500-12

Corcoran K, Wang X, Lybarger L. Jun 2009. Adapter-mediated substrate selection for endoplasmic reticulum-associated degradation. J Biol Chem, 284:17475-87

Mitaksov V Truscott SM Lybarger L Connolly JM Hansen TH Fremont DH. Aug 2007. Structural engineering of pMHC reagents for T cell vaccines and diagnostics. Chem Biol, 14:909-22