CD27 Instructs CD4+ T Cells to Provide Help for the Memory CD8+ T Cell Response after Protein Immunization

Abstract

For optimal quality, memory CD8+ T cells require CD4+ T cell help. We have examined whether CD4+ T cells require CD27 to deliver this help, in a model of intranasal OVA protein immunization. CD27 deficiency reduced the capacity of CD4+ T cells to support Ag-specific CD8+ T cell accumulation at the tissue site after primary and secondary immunization. CD27-dependent CD4+ T cell help for the memory CD8+ T cell response was delivered during priming. It did not detectably affect formation of CD8+ memory T cells, but promoted their secondary expansion. CD27 improved survival of primed CD4+ T cells, but its contribution to the memory CD8+ T cell response relied on altered CD4+ T cell quality rather than quantity. CD27 induced a Th1-diagnostic gene expression profile in CD4+ T cells, which included the membrane molecule MS4A4B. Accordingly, CD27 increased the frequency of IFN-γ- and IL-2-producing CD4+ T cells. It did not affect CD40L expression. Strikingly, MS4A4B was also identified as a unique marker of CD8+ memory T cells that had received CD27-proficient CD4+ T cell help during the primary response. This apparent imprinting effect suggests a role for MS4A4B as a downstream effector in CD27-dependent help for CD8+ T cell memory.

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

“…For gene-expression profiling, WT or Cd27 2/2 OT-I mice were immunized intranasally with 500 mg OVA protein and 1 mg cholera toxin (Sigma) in 50 ml HBSS (30). For the experiments depicted in Figs.…”

“…For in vitro cultures, T cells were purified from spleens and lymph nodes, as described previously (30), or with the BD IMag mouse CD8 T lymphocyte enrichment kit -DM (BD; cat. no.…”

“…At the tissue effector site, CD27/CD70 costimulation improves the survival of effector CD8 + T cells by autocrine IL-2 signaling (29). In CD4 + T cells, CD27/CD70 costimulation supports clonal expansion, as well as Th1-type effector development and help for the memory CD8 + T cell response (30,31). In an unbiased search for CD27-regulated transcripts in CD8 + T cells, we identified the Cxcl10 gene as one of the major CD27 target genes.…”

The Pim Kinase Pathway Contributes to Survival Signaling in Primed CD8+ T Cells upon CD27 Costimulation

“…Amplified RNA was generated from purified WT and Cd27 2/2 OT-I T cells as described (40). Microarrays spotted with the Operon v3 oligonucleotide library were obtained from the central microarray facility of The Netherlands Cancer Institute (http://microarrays.nki.nl).…”

CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response

“…These data indicate that a synergistic relationship exists between CD27 stimulation and CD4 + T cell help. CD27 signaling has been previously shown to drive T H 1 polarization in mouse 33 and human 34 CD4 + T cells by upregulating IL-12Rβ2 and T-bet expression and was also found to enhance their helper activity towards CD8 + T cells. 35 Additionally, we surmise that CD4 + T cell help may render CD8 + T cells more sensitive to CD27 signaling, thus amplifying the effect of αhCD27 on the CD8 + T cell response compared to the effect that αhCD27 would have in the absence of CD4 + T cell help.…”