Research and Clinical Interests
There are currently five major interests in the Eisenlohr laboratory all of which relate to T cell recognition of antigen.
Processing and presentation for class I-restricted T cell recognition.
Most effort is being expended to determine the cellular elements involved in antigen processing and how subcellular location impacts the efficiency of antigen processing. These issues are being addressed through expression of genetically-manipulated influenza proteins bearing known class I-restricted T cell determinants. The approach has provided important information about the proteases that contribute to antigen processing and the efficiency with which proteins and protein fragments traffick within the cell.
Processing and loading compartments involved in presentation of MHC class II-restricted antigenic peptides.
We are utilizing two glycoproteins of influenza virus, hemagglutinin (HA) and neuraminidase (NA) 1) to identify the subcellular compartments within the cell where antigen becomes available for binding to class II molecules and the compartments where binding takes place, and 2) to determine the extent to which these processes differ in different cell types and when the antigen is taken up from the extracellular space vs. expressed in the antigen presenting cell itself.
The expression and response to "cryptic" MHC class I-restricted epitopes.
MHC class I-restricted cytotoxic T lymphocytes (CTL) are exquisitely sensitive to low levels of antigens and we and others have demonstrated that they can be triggered by the products of aberrant gene expression, such as alternative splicing, exon translation, alternative start codon usage and frameshifting. We hypothesize that these aberrant translation products play an important role in defining the world of "self" and may be involved in triggering autoimmunity. In a collaboration with the laboratory of Dr. Raymond Gesteland (U. of Utah) we are currently focusing on one of these mechanisms, ribosomal frameshifting, and its role in T cell activation.
Dynamics of CD8+ T cell responses.
Using tools generated in association with project 1, we are now investigating the impact that antigen dose has upon the magnitude of the T cell response and the character of the resulting memory population.
Thyroid cancer and autoimmunity.
We are collaborating with Dr. Jay Rothstein (Department of Otolaryngology-HNS) to determine basis for the link between autoimmune thyroiditis and thyroid neoplasia. Our role in this project has been to design proteins that are expressed in thyroid tissue of transgenic mice that can be used to trigger autoimmune thyroiditis. Depending upon the engineering of these proteins, that impacts the way they are processed for presentation to T cells, we expect the character of the autoimmune response to vary. We anticipate that many of the same approaches taken in this project will apply to a recently-initiated collaboration with Dr. Scott Waldman (Department of Medicine/Director of Clinical Pharmacology) to address similar questions in colon cancer.
Findings related to these five projects will contribute important information to the areas of vaccine design, tissue transplantation, autoimmune therapy, and immune-based anti-cancer strategies.