CD8+ CTL play a critical role as effectors in limiting viral infections, conveying anti-tumor immunity, and contributing to autoimmunity. CD8+ CTL are triggered by antigen-derived peptides (epitopes) held at the surface of antigen-bearing cells by MHC class I molecules. In most cases the first step in epitope generation is degradation of antigen within the cytosol. Resultant fragments are then actively transported to the lumen of the endoplasmic reticulum where they bind to nascent MHC class I molecules provided they meet stringent length and sequence requirements. The heterotrimeric complexes are then transported to the cell surface where they are contacted by T cells with appropriate receptor specificities. In contrast to some previous findings, Dr. Eisenlohr's studies indicate that the antigen processing machinery dictates the quality of the antigenic epitopes generated. They hypothesize that 1) flanking sequences have an impact upon immunogenicity of epitopes, and that viruses and tumor cells use mutation of flanking sequences to evade CD8+ CTL; and 2) the study of proximal and distal flanking sequence effects provides valuable insight into the nature of the antigen processing machinery and powerful tools for identifying specific components of the machinery. To test these hypotheses, the investigators will: 1) determine whether there are general rules that govern the influence of sequences neighboring an epitope, 2) directly test in vivo the impact that flanking sequences have upon recruitment of CD8+ CTL precursors, memory CTL, and resistance to viral and tumor challenge, 3) determine whether the blocks in processing conferred by local flanking residues can be attributed to proteasome specificity, and whether the blocks in processing conferred by local flanking residues can be attributed to proteasome specificity and whether other proteases are implicated in antigen processing, and 4) identify and characterize sequences that strongly influence, positively and negatively, presentation of distal epitopes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Deckhut Augustine, Alison M
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Thomas Jefferson University
Schools of Medicine
United States
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Goodenough, Elliot; Robinson, Tara M; Zook, Matthew B et al. (2014) Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3' UTR. Proc Natl Acad Sci U S A 111:5670-5
Huang, Lan; Kuhls, Matthew C; Eisenlohr, Laurence C (2011) Hydrophobicity as a driver of MHC class I antigen processing. EMBO J 30:1634-44
Huang, Lan; Marvin, Julie M; Tatsis, Nia et al. (2011) Cutting Edge: Selective role of ubiquitin in MHC class I antigen presentation. J Immunol 186:1904-8
Testa, James S; Apcher, Geraud S; Comber, Joseph D et al. (2010) Exosome-driven antigen transfer for MHC class II presentation facilitated by the receptor binding activity of influenza hemagglutinin. J Immunol 185:6608-16
Wherry, E John; Golovina, Tatiana N; Morrison, Susan E et al. (2006) Re-evaluating the generation of a ""proteasome-independent"" MHC class I-restricted CD8 T cell epitope. J Immunol 176:2249-61
Zook, Matthew B; Howard, Michael T; Sinnathamby, Gomathinayagam et al. (2006) Epitopes derived by incidental translational frameshifting give rise to a protective CTL response. J Immunol 176:6928-34
Golovina, Tatiana N; Morrison, Susan E; Eisenlohr, Laurence C (2005) The impact of misfolding versus targeted degradation on the efficiency of the MHC class I-restricted antigen processing. J Immunol 174:2763-9
Powell Jr, Daniel J; Eisenlohr, Laurence C; Rothstein, Jay L (2003) A thyroid tumor-specific antigen formed by the fusion of two self proteins. J Immunol 170:861-9
Golovina, Tatiana N; Wherry, E John; Bullock, Timothy N J et al. (2002) Efficient and qualitatively distinct MHC class I-restricted presentation of antigen targeted to the endoplasmic reticulum. J Immunol 168:2667-75
Wherry, E John; McElhaugh, Michael J; Eisenlohr, Laurence C (2002) Generation of CD8(+) T cell memory in response to low, high, and excessive levels of epitope. J Immunol 168:4455-61

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