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 J. Bentrem; Khashayarsha Khazaie

doi:10.1073/pnas.0913683107

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 J. Bentrem, Khashayarsha Khazaie

Allergy, Asthma and Clinical Immunology

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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 language	English (US)
Pages (from-to)	6430-6435
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	107
Issue number	14
DOIs	https://doi.org/10.1073/pnas.0913683107
State	Published - Apr 6 2010

Keywords

Interleukin 17
Interleukin 6

ASJC Scopus subject areas

General

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10.1073/pnas.0913683107

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Blatner, N. R., Bonertz, A., Beckhove, P., Cheon, E. C., Krantz, S. B., Strouch, M., Weitz, J., Koch, M., Halverson, A. L., Bentrem, D. J., & Khazaie, K. (2010). In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 107(14), 6430-6435. https://doi.org/10.1073/pnas.0913683107

Blatner, NR, Bonertz, A, Beckhove, P, Cheon, EC, Krantz, SB, Strouch, M, Weitz, J, Koch, M, Halverson, AL, Bentrem, DJ & Khazaie, K 2010, 'In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 14, pp. 6430-6435. https://doi.org/10.1073/pnas.0913683107

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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.",

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AU - Strouch, Matthew

AU - Weitz, Juergen

AU - Koch, Moritz

AU - Halverson, Amy L.

AU - Bentrem, David J.

AU - Khazaie, Khashayarsha

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

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Keywords

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