In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction

Nichole R. Blatner, Andreas Bonertz, Philipp Beckhove, Eric C Cheon, Seth B. Krantz, Matthew Strouch, Juergen Weitz, Moritz Koch, Amy L Halverson, David Jason Bentrem, Khashayarsha Khazaie*

*Corresponding author for this work

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proin-flammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.

Original languageEnglish (US)
Pages (from-to)6430-6435
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number14
DOIs
StatePublished - Apr 6 2010

Fingerprint

Regulatory T-Lymphocytes
Mast Cells
Colorectal Neoplasms
Interleukin-6
Polyps
Cell Degranulation
Coculture Techniques
Autoimmunity
Interleukin-10
Interleukin-2
Cell Culture Techniques
Bone Marrow
Inflammation
T-Lymphocytes

Keywords

  • Interleukin 17
  • Interleukin 6

ASJC Scopus subject areas

  • General

Cite this

Blatner, Nichole R. ; Bonertz, Andreas ; Beckhove, Philipp ; Cheon, Eric C ; Krantz, Seth B. ; Strouch, Matthew ; Weitz, Juergen ; Koch, Moritz ; Halverson, Amy L ; Bentrem, David Jason ; Khazaie, Khashayarsha. / In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 14. pp. 6430-6435.
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In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. / Blatner, Nichole R.; Bonertz, Andreas; Beckhove, Philipp; Cheon, Eric C; Krantz, Seth B.; Strouch, Matthew; Weitz, Juergen; Koch, Moritz; Halverson, Amy L; Bentrem, David Jason; Khazaie, Khashayarsha.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 14, 06.04.2010, p. 6430-6435.

Research output: Contribution to journalArticle

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AU - Blatner, Nichole R.

AU - Bonertz, Andreas

AU - Beckhove, Philipp

AU - Cheon, Eric C

AU - Krantz, Seth B.

AU - Strouch, Matthew

AU - Weitz, Juergen

AU - Koch, Moritz

AU - Halverson, Amy L

AU - Bentrem, David Jason

AU - Khazaie, Khashayarsha

PY - 2010/4/6

Y1 - 2010/4/6

N2 - T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proin-flammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.

AB - T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proin-flammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell-suppressive properties. IL6 and IL17 are not needed in this process.

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