Regulation of A1 by OX40 contributes to CD8(+) T cell survival and anti-tumor activity

PLoS One. 2013 Aug 1;8(8):e70635. doi: 10.1371/journal.pone.0070635. Print 2013.

Abstract

The TNFR family member OX40 (CD134) is critical for optimal clonal expansion and survival of T cells. However, the intracellular targets of OX40 in CD8 T cells are not fully understood. Here we show that A1, a Bcl-2 family protein, is regulated by OX40 in effector CD8 T cells. In contrast to wild-type T cells, OX40-deficient CD8 T cells failed to maintain A1 expression driven by antigen. Conversely, enforced OX40 stimulation promoted A1 expression. In both situations, the expression of A1 directly correlated with CD8 T cell survival. In addition, exogenous expression of A1 in OX40-deficient CD8 T cells reversed their survival defect in vitro and in vivo. Moreover, forced expression of A1 in CD8 T cells from OX40-deficient mice restored the ability of these T cells to suppress tumor growth in a murine model. These results indicate that OX40 signals regulate CD8 T cell survival at least in part through maintaining expression of the anti-apoptotic molecule A1, and provide new insight into the mechanism by which OX40 may impact anti-tumor immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Survival
  • Gene Knockout Techniques
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Receptors, OX40 / deficiency
  • Receptors, OX40 / genetics
  • Receptors, OX40 / metabolism*
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, OX40
  • Tumor Suppressor Proteins