title: The CD8+ T-cell response to lymphocytic choriomeningitis virus involves the L antigen: uncovering new tricks for an old virus.
abstract: CD8(+) T-cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2(b) mice. Although antigen-specific responses against LCMV infection are well studied, we found that a significant fraction of the CD8(+) CD44(hi) T-cell response to LCMV in H-2(b) mice was not accounted for by known epitopes. We screened peptides predicted to bind major histocompatibility complex class I and overlapping 15-mer peptides spanning the complete LCMV proteome for gamma interferon (IFN-gamma) induction from CD8(+) T cells derived from LCMV-infected H-2(b) mice. We identified 19 novel epitopes. Together with the 9 previously known, these epitopes account for the total CD8(+) CD44(hi) response. Thus, bystander T-cell activation does not contribute appreciably to the CD8(+) CD44(hi) pool. Strikingly, 15 of the 19 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8(+) T cells, whereas IFN-gamma production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8(+) T-cell response is more complex than previously appreciated.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Maya F
authors.initials: MF
authors.lastname: Kotturi
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Fernando
authors.initials: F
authors.lastname: Buendia-Laysa
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Carla
authors.initials: C
authors.lastname: Oseroff
authors.forename: Jason
authors.initials: J
authors.lastname: Botten
authors.forename: Howard
authors.initials: H
authors.lastname: Grey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buchmeier
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D012321:DNA-Directed RNA Polymerases / Q000276:immunology; D004195:Disease Models, Animal; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000821:virology; D010948:Viral Plaque Assay
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D018960:Hyaluronan Receptors; D007371:Interferon-gamma; D012321:DNA-Directed RNA Polymerases