Bystander activation and anti-tumor effects of CD8+ T cells following interleukin-2 based immunotherapy is independent of CD4+ T cell help

Arta M. Monjazeb, Julia K. Tietze, Steven K. Grossenbacher, Hui Hua Hsiao, Anthony E. Zamora, Annie Mirsoian, Brent Koehn, Bruce R. Blazar, Jonathan M. Weiss, Robert H. Wiltrout, Gail D. Sckisel, William J. Murphy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander- activated" (CD8+CD44high) T cells displaying a CD25-NKG2D+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4+ T cell help for antigen-specific CD8+ T cell expansion, little is known regarding the role of CD4+ T cells in antigen-nonspecific bystander-memory CD8+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non- CD4 depleted mice. Expanded bystander-memory CD8+ T cells upregulated PD-1 in the absence of CD4+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8+ T cells. Interestingly, compared to CD8+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8+ T cell expansion, CD4+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.

Original languageEnglish (US)
Article numbere102709
JournalPloS one
Issue number8
StatePublished - Aug 13 2014


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