Endogenous antigen processing drives the primary CD4+ T cell response to influenza.

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This article has been peer reviewed. It was published in: Nature Medicine.

Volume 21, Issue 10, 1 October 2015, Pages 1216-1222.

The published version is available at DOI: 10.1038/nm.3958

Copyright © 2015 2015 Nature America, Inc. All rights reserved.


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.

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