IFN-gamma inhibits IL-4-induced type 2 cytokine expression by CD8 T cells in vivo and modulates the anti-tumor response

J Immunol. 2010 Jul 15;185(2):998-1004. doi: 10.4049/jimmunol.0903372. Epub 2010 Jun 18.


Activation of naive CD8 T cells in vitro in the presence of IL-4 induces type 2 cytokine expression, loss of CD8 expression, and reduced cytolytic potential. This represents a major shift from the canonical phenotype of effector CD8 T cells. It has not been established, however, whether IL-4 can induce comprehensive type 2 cytokine expression by CD8 T cells in vivo, nor whether the effects of IL-4 on type 2 cytokine production by CD8 T cells can be inhibited by IFN-gamma. Furthermore, disparate results have been reported regarding the anti-tumor ability of type 2 polarized effector CD8 T cells, and the effects of IFN-gamma in this respect remain unknown. To address these questions, wild-type or IFN-gamma-deficient OVA-specific CD8(+) T cells were activated in RAG-2(-/-) gamma c(-/-) recipients with control or IL-4-expressing OVA(+) tumor cells, and then transferred to secondary recipients for tumor challenge. Tumor-derived IL-4 induced the expression of type 2 cytokines and the transcription factor GATA-3 by responding CD8 T cells while reducing their CD8 coreceptor expression and ability to eliminate a secondary tumor challenge. Each of these effects of IL-4 was exaggerated in IFN-gamma-deficient, compared with wild-type, CD8 T cells. The results demonstrate that endogenous IFN-gamma counteracts the induction of type 2 cytokines and the downregulation of both CD8 coreceptor levels and the anti-tumor response in CD8 T cells exposed to IL-4 during activation in vivo. These findings may explain the anomalies in the reported functional phenotype of type 2 polarized CD8 T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Flow Cytometry
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / immunology
  • GATA3 Transcription Factor / metabolism
  • Gene Expression
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Reverse Transcriptase Polymerase Chain Reaction


  • Cytokines
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Interleukin-2
  • Interleukin-4
  • Interferon-gamma