Vaccination Produces CD4 T Cells with a Novel CD154-CD40-Dependent Cytolytic Mechanism

• Published in: The Journal of immunology (1950) Vol. 195; no. 7; pp. 3190 - 3197
• Main Authors: Coler, Rhea N, Hudson, Thomas, Hughes, Sean, Huang, Po-Wei D, Beebe, Elyse A, Orr, Mark T
• Format: Journal Article
• Language: English
• Published: United States 01-10-2015
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; CD4-Positive T-Lymphocytes - immunology; CD40 Antigens - biosynthesis; CD40 Antigens - immunology; CD40 Ligand - biosynthesis; CD40 Ligand - immunology; Cytotoxins - immunology; Fas Ligand Protein - immunology; Granzymes - biosynthesis; Granzymes - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, TNF-Related Apoptosis-Inducing Ligand - immunology; T-Box Domain Proteins - immunology; T-Lymphocytes, Cytotoxic - immunology; Th1 Cells - immunology; TNF-Related Apoptosis-Inducing Ligand - immunology; Vaccination
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501118

The discovery of new vaccines against infectious diseases and cancer requires the development of novel adjuvants with well-defined activities. The TLR4 agonist adjuvant GLA-SE elicits robust Th1 responses to a variety of vaccine Ags and is in clinical development for both infectious diseases and cancer. We demonstrate that immunization with a recombinant protein Ag and GLA-SE also induces granzyme A expression in CD4 T cells and produces cytolytic cells that can be detected in vivo. Surprisingly, these in vivo CTLs were CD4 T cells, not CD8 T cells, and this cytolytic activity was not dependent on granzyme A/B or perforin. Unlike previously reported CD4 CTLs, the transcription factors Tbet and Eomes were not necessary for their development. CTL activity was also independent of the Fas ligand-Fas, TRAIL-DR5, and canonical death pathways, indicating a novel mechanism of CTL activity. Rather, the in vivo CD4 CTL activity induced by vaccination required T cell expression of CD154 (CD40L) and target cell expression of CD40. Thus, vaccination with a TLR4 agonist adjuvant induces CD4 CTLs, which kill through a previously unknown CD154-dependent mechanism.