Research Abstract:
Research in my lab focuses on the development and function of CD8 T lymphocytes, which provide a major host defense against intracellular pathogens and tumors. Major histocompatibility complex class I molecules (MHCI) bind intracellular peptides derived from self or foreign proteins (viral or tumor) and display peptide/MHCI complexes on the cell surface for recognition by CD8 T cells. We have developed a strategy to create a more immunogenic peptide/MHCI complex by expressing MHCI molecules as single chain trimers (SCT) consisting of antigenic peptide, beta2m, and heavy chain attached with flexible linkers. These SCT are potent stimulators of peptide-specific cytotoxic CD8 T cells and antibodies specific for peptide/MHCI. We are currently testing these SCT for their potential as DNA vaccines against viruses and tumors.
We have also expressed SCT in vivo as transgenes to define how development of CD8 T cells is influenced by the expression of a single peptide/MHCI complex. During development in the thymus, CD8 T cells establish exquisite specificity against pathogens while maintaining tolerance to self. The role of peptide in thymic positive selection of the T cell repertoire is at the heart of several unresolved issues. Therefore, we will determine how selection on a single peptide/MHCI complex influences the size, diversity, and specificity of the CD8 T cell repertoire. We will also establish the relationship between the selecting and cognate peptides and determine the impact of structural similarity of the peptides on the development and function of the CD8 T cell repertoire.
Selected Publications:
Truscott, S. M., L. Lybarger, J. M. Martinko, V. E. Mitaksov, D. M. Kranz, J. M. Connolly, D. H. Fremont, and T. H. Hansen. 2007. Disulfide bond engineering to trap peptides in the MHC class I binding groove. J Immunol 2007 178: 6280-6289.
Primeau T, Myers NB, Yu YY, et al. Applications of MHC class I molecules expressed as single chains. Immunol Res 2005 32: 109-122.
Hornell TMC, Myers N, Hansen TH, Connolly JM. Homology between an alloantigen and a self-allele calibrates the avidity of the alloreactive T cell repertoire independent of TCR affinity. J Immunol 2003 170: 4506-4514.
Yu YY, Netuschil N, Lybarger L, Connolly JM, Hansen TH. Cutting edge: Single chain trimers of MHC-I molecules form stable structures that potently stimulate antigen-specific T cells and B cells. J Immunol 2002 168: 3145-3149.
Hornell TM, Martin SM, Myers NB, Connolly JM. Peptide length variants p2Ca and QL9 present distinct conformations to Ld-specific T cells. J Immunol 2001 167: 4207-4214.
Last Updated: 02/27/2008 |