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

Apte, Simon H., Groves, Penny, Olver, Stuart, Baz, Adriana, Doolan, Denise L., Kelso, Anne, and Kienzle, Norbert (2010) IFN-γ inhibits IL-4-induced type 2 cytokine expression by CD8 T cells in vivo and modulates the anti-tumor response. Journal of Immunology, 185 (2). pp. 998-1004.

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Abstract

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-γ. Furthermore, disparate results have been reported regarding the anti-tumor ability of type 2 polarized effector CD8 T cells, and the effects of IFN-γ in this respect remain unknown. To address these questions, wild-type or IFN-γ–deficient OVA-specific CD8⁺ T cells were activated in RAG-2⁻/⁻ γc⁻/⁻ 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-γ–deficient, compared with wild-type, CD8 T cells. The results demonstrate that endogenous IFN-γ 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.

Item ID: 42726
Item Type: Article (Refereed Research - C1)
ISSN: 1550-6606
Funders: Cooperative Research Centre for Vaccine Technology (CRCVT), National Health and Medical Research Council (NHMRC) Australia, Cancer Council Queensland (CCQ), Australian Rotary Health Research Fund (ARHRF) Basil Shaw Fellowship, Pfizer Australia Senior Research Fellowship (PASRF)
Date Deposited: 24 Mar 2016 02:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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