Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells

Nicholas M. Provine, Rafael A. Larocca, Malika Aid, Pablo Penaloza-MacMaster, Alexander Badamchi-Zadeh, Erica N. Borducchi, Kathleen B. Yates, Peter Abbink, Marinela Kirilova, David Ng'ang'a, Jonathan Bramson, W. Nicholas Haining, Dan H. Barouch*

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

CD4+ T cell help is critical for optimal CD8+ T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8+ T cell responses in the absence of CD4+ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4+ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8+ T cell functionality and differentiation. Unhelped CD8+ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8+ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4+ T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4+ T cell help is required to promote both the expansion and acquisition of effector functions by CD8+ T cells, which is accomplished by preventing immediate dysfunction.

Original languageEnglish (US)
Pages (from-to)1809-1822
Number of pages14
JournalJournal of Immunology
Volume197
Issue number5
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Provine, N. M., Larocca, R. A., Aid, M., Penaloza-MacMaster, P., Badamchi-Zadeh, A., Borducchi, E. N., Yates, K. B., Abbink, P., Kirilova, M., Ng'ang'a, D., Bramson, J., Haining, W. N., & Barouch, D. H. (2016). Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells. Journal of Immunology, 197(5), 1809-1822. https://doi.org/10.4049/jimmunol.1600591