Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Monjazeb, Arta M1
  • Tietze, Julia K2
  • Grossenbacher, Steven K2
  • Hsiao, Hui-Hua2
  • Zamora, Anthony E2
  • Mirsoian, Annie2
  • Koehn, Brent3
  • Blazar, Bruce R3
  • Weiss, Jonathan M4
  • Wiltrout, Robert H4
  • Sckisel, Gail D2
  • Murphy, William J5
  • 1 Department of Radiation Oncology School of Medicine, University of California Davis, Sacramento, California, United States of America. , (United States)
  • 2 Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America. , (United States)
  • 3 Department of Pediatrics, Division of Blood and Marrow Transplantation and Masonic Cancer Center, University of Minnesota, Minneapolis, Massachusetts, United States of America. , (United States)
  • 4 Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, United States of America. , (United States)
  • 5 Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California, United States of America. , (United States)
Type
Published Article
Journal
PLoS ONE
Publisher
Public Library of Science
Publication Date
Jan 01, 2014
Volume
9
Issue
8
Identifiers
DOI: 10.1371/journal.pone.0102709
PMID: 25119341
Source
Medline
Language
English
License
Unknown

Abstract

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.

Report this publication

Statistics

Seen <100 times