title: Endogenous antigen processing drives the primary CD4+ T cell response to influenza.
abstract: By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and γ-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Asha Purnima V
authors.initials: AP
authors.lastname: Ganesan
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Luckashenak
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mendonca
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007251:Influenza, Human / Q000276:immunology*; D051379:Mice; D014771:Virion / Q000276:immunology
chemical_list: D000941:Antigens