The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer.
OBJECTIVE
An efficient cytolytic T cell function is essential for immune mediated rejection of colorectal cancer. However, the molecular mechanisms driving T cell mediated cancer rejection are still poorly understood. Here, we assessed the relevance of the T-box transcription factor eomesodermin in colorectal cancer. METHODS/ RESULTS: By analysing tissue probes from 88 different colorectal tumours, a significant (p<0.02) inverse correlation between eomesodermin expression in colorectal cancers and the presence of lymph node metastases could be shown, whereas no such correlation was noted for the master transcription factor of regulatory T cells, FoxP3 and CD8 alpha expression. To evaluate whether this effect might be due to effects of eomesodermin on tumour infiltrating CD8 T cells, we subsequently analysed the regulated expression and function of this transcription factor in human T cells. Whereas overexpression of this factor induced perforin but not granzyme expression, siRNA mediated suppression of eomesodermin expression led to significantly reduced IFN-gamma production, perforin levels and cytolytic activity of CD8 T cells. Furthermore, TGF-beta and IL4 could be identified as important inducer of eomesodermin expression.


CONCLUSIONS
These data define for the first time a regulatory role of eomesodermin for CD8 T cell activity in humans. Our findings are consistent with a model in which eomesodermin expression in tumour infiltrating T cells regulates cytolytic functions of CD8 T cells via perforin expression. These data provide novel insights into control mechanisms governing the functional activity of human CD8 T lymphocytes via T-box transcription factors in cancer.
Atreya
Imke
I
I. Department of Medicine, University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.
Schimanski
Carl C
CC
Becker
Christoph
C
Wirtz
Stefan
S
Dornhoff
Heike
H
Schnürer
Elke
E
Berger
Martin R
MR
Galle
Peter R
PR
Herr
Wolfgang
W
Neurath
Markus F
MF
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008207:Lymphatic Metastasis / Q000276:immunology*; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C491199:EOMES protein, human; D020825:T-Box Domain Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4