CD154 and IL-2 signaling of CD4+ T cells play a critical role in multiple phases of CD8+ CTL responses following adenovirus vaccination.
Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8(+) cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4(+) T cell-provided signals in the development of functional CD8(+) CTL responses remain unclear. To explore CD4(+) T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4(+) T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4(+) T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4(+) T help in CD4(+) T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4(+) T cell-produced IL-2 and CD154 signals. Adoptive transfer of "helped" or "unhelped" effector and memory CTLs into naïve CD4(+) T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4(+) T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4(+) T cell environment, particularly involving memory CD4(+) T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4(+) T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4(+) T cell population and function.
Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Channakeshava
C
Sokke Umeshappa
Roopa
R
Hebbandi Nanjundappa
Yufeng
Y
Xie
Andrew
A
Freywald
Yulin
Y
Deng
Hong
H
Ma
Jim
J
Xiang
D000256:Adenoviridae / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014611:Vaccination
D015704:CD4 Antigens; D007376:Interleukin-2; D023201:CD40 Ligand; D010047:Ovalbumin