IFN-gamma inhibits IL-4-induced type 2 cytokine expression by CD8 T cells in vivo and modulates the anti-tumor response.
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.
Apte
Simon H
SH
Queensland Institute of Medical Research, Brisbane, Queensland, Australia. Simon.Apte@qimr.edu.au
Groves
Penny
P
Olver
Stuart
S
Baz
Adriana
A
Doolan
Denise L
DL
Kelso
Anne
A
Kienzle
Norbert
N
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma