| 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.
Keywords: antigen processing, and presentation, MHC class I molecules, MHC class II molecules, influenza virus
Golovina TN, Morrison SE, Eisenlohr LC. The impact of misfolding versus targeted degradation on the efficiency o the MHC class I-restricted antigen processing. J Immunol 2005 Mar 1;174(5):2763-9. ( Abstract )
Tewari MK, Sinnathamby G, Rajagopal D, Eisenlohr LC. A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent. Nat Immunol 2005 Mar;6(3):287-94. Epub 2005 Feb 13.. ( Abstract )
Sinnathamby G, Maric M, Cresswell P, Eisenlohr LC. Differential requirements for endosomal reduction in the presentation o two H2-E(d)-restricted epitopes from influenza hemagglutinin. J Immunol 2004 Jun 1;172(11):6607-14. ( Abstract )
Tatsis N, Sinnathamby G, Eisenlohr LC. Vaccinia virus as a tool for immunologic studies. Methods Mol Biol 2004;269:267-88.. ( Abstract )
Sinnathamby G, Eisenlohr LC. Presentation by recycling MHC class II molecules of an influenza hemagglutinin-derived epitope that is revealed in the early endosome by acidification. J Immunol 2003 Apr 1;170(7):3504-13.. ( Abstract )
Wherry EJ, McElhaugh MJ, Eisenlohr LC. Generation of CD8(+) T cell memory in response to low, high, and excessiv levels of epitope. J Immunol 2002 May 1;168(9):4455-61. ( Abstract )
Golovina TN, Wherry EJ, Bullock TN, Eisenlohr LC. Efficient and qualitatively distinct MHC class I-restricted presentation of antigen targeted to the endoplasmic reticulum. J Immunol 2002 Mar 15;168(6):2667-75.. ( Abstract )
Wherry EJ, Rajagopal D, Eisenlohr LC. Use of vaccinia virus expression vectors to investigate antigen processin and presentation. Methods Mol Biol 2001;156:89-109. ( Abstract )
Grandea AG 3rd, Golovina TN, Hamilton SE, Sriram V, Spies T, Brutkiewicz RR, Harty JT, Eisenlohr LC, Van Kaer L. Impaired assembly yet normal trafficking of MHC class I molecules i Tapasin mutant mice. Immunity 2000 Aug;13(2):213-22. ( Abstract )
Mastrangelo MJ, Eisenlohr LC, Gomella L, Lattime EC. Poxvirus vectors: orphaned and underappreciated. J Clin Invest 2000 Apr;105(8):1031-4. ( Abstract )
Wherry EJ, Puorro KA, Porgador A, Eisenlohr LC. The induction of virus-specific CTL as a function of increasing epitop expression: responses rise steadily until excessively high levels o epitope are attained. J Immunol 1999 Oct 1;163(7):3735-45. ( Abstract )
Chianese-Bullock KA, Russell HI, Moller C, Gerhard W, Monaco JJ, Eisenlohr LC. Antigen processing of two H2-IEd-restricted epitopes is differentiall influenced by the structural changes in a viral glycoprotein. J Immunol 1998 Aug 15;161(4):1599-607. ( Abstract )
Yellen-Shaw AJ, Laughlin CE, Metrione RM, Eisenlohr LC. Murine transporter associated with antigen presentation (TAP) preference influence class I-restricted T cell responses. J Exp Med 1997 Nov 17;186(10):1655-62. ( Abstract )
Sato T, Bullock TN, Eisenlohr LC, Mastrangelo MJ, Berd D. Dinitrophenyl-modified autologous melanoma vaccine induces a T cel response to hapten-modified, melanoma peptides. Clin Immunol Immunopathol 1997 Dec;85(3):265-72. ( Abstract )
Bullock TN, Patterson AE, Franlin LL, Notidis E, Eisenlohr LC. Initiation codon scanthrough versus termination codon readthroug demonstrates strong potential for major histocompatibility complex clas I-restricted cryptic epitope expression. J Exp Med 1997 Oct 6;186(7):1051-8. ( Abstract )
Yellen-Shaw AJ, Wherry EJ, Dubois GC, Eisenlohr LC. Point mutation flanking a CTL epitope ablates in vitro and in viv recognition of a full-length viral protein. J Immunol 1997 Apr 1;158(7):3227-34. ( Abstract )
Yellen-Shaw AJ, Eisenlohr LC. Regulation of class I-restricted epitope processing by local or distal flanking sequence. J Immunol 1997 Feb 15;158(4):1727-33.. ( Abstract )
Bullock TN, Eisenlohr LC. Ribosomal scanning past the primary initiation codon as a mechanism fo expression of CTL epitopes encoded in alternative reading frames. J Exp Med 1996 Oct 1;184(4):1319-29. ( Abstract )
Lattime EC, Lee SS, Eisenlohr LC, Mastrangelo MJ. In situ cytokine gene transfection using vaccinia virus vectors. Semin Oncol 1996 Feb;23(1):88-100.. ( Abstract )
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