ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

Melody Cheong; Kate H. Gartlan; Jason S. Lee; Siok Keen Tey; Ping Zhang; Rachel D. Kuns; Christopher E. Andoniou; Jose Paulo Martins; Karshing Chang; Vivien R. Sutton; Greg Kelly; Antiopi Varelias; Slavica Vuckovic; Kate A. Markey; Glen M. Boyle; Mark J. Smyth; Christian R. Engwerda; Kelli P.A. MacDonald; Joseph A. Trapani; Mariapia A. Degli-Esposti; Motoko Koyama; Geoffrey R. Hill

doi:10.1158/2326-6066.CIR-19-0653

ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

Melody Cheong, Kate H. Gartlan, Jason S. Lee, Siok Keen Tey, Ping Zhang, Rachel D. Kuns, Christopher E. Andoniou, Jose Paulo Martins, Karshing Chang, Vivien R. Sutton, Greg Kelly, Antiopi Varelias, Slavica Vuckovic, Kate A. Markey, Glen M. Boyle, Mark J. Smyth, Christian R. Engwerda, Kelli P.A. MacDonald, Joseph A. Trapani, Mariapia A. Degli-EspostiMotoko Koyama, Geoffrey R. Hill

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

7 Citations (Scopus)

Abstract

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

Original language	English
Pages (from-to)	1085-1098
Number of pages	14
Journal	Cancer Immunology Research
Volume	8
Issue number	8
DOIs	https://doi.org/10.1158/2326-6066.CIR-19-0653
Publication status	Published - Aug 2020

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Cheong, M., Gartlan, K. H., Lee, J. S., Tey, S. K., Zhang, P., Kuns, R. D., Andoniou, C. E., Martins, J. P., Chang, K., Sutton, V. R., Kelly, G., Varelias, A., Vuckovic, S., Markey, K. A., Boyle, G. M., Smyth, M. J., Engwerda, C. R., MacDonald, K. P. A., Trapani, J. A., ... Hill, G. R. (2020). ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome. Cancer Immunology Research, 8(8), 1085-1098. https://doi.org/10.1158/2326-6066.CIR-19-0653

@article{950b40e9cf6d4a01b45a8d1a031f671f,

title = "ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome",

abstract = "The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.",

author = "Melody Cheong and Gartlan, {Kate H.} and Lee, {Jason S.} and Tey, {Siok Keen} and Ping Zhang and Kuns, {Rachel D.} and Andoniou, {Christopher E.} and Martins, {Jose Paulo} and Karshing Chang and Sutton, {Vivien R.} and Greg Kelly and Antiopi Varelias and Slavica Vuckovic and Markey, {Kate A.} and Boyle, {Glen M.} and Smyth, {Mark J.} and Engwerda, {Christian R.} and MacDonald, {Kelli P.A.} and Trapani, {Joseph A.} and Degli-Esposti, {Mariapia A.} and Motoko Koyama and Hill, {Geoffrey R.}",

year = "2020",

month = aug,

doi = "10.1158/2326-6066.CIR-19-0653",

language = "English",

volume = "8",

pages = "1085--1098",

journal = "Cancer Immunology Research",

issn = "2326-6066",

publisher = "American Association for Cancer Research (AACR)",

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Cheong, M, Gartlan, KH, Lee, JS, Tey, SK, Zhang, P, Kuns, RD, Andoniou, CE, Martins, JP, Chang, K, Sutton, VR, Kelly, G, Varelias, A, Vuckovic, S, Markey, KA, Boyle, GM, Smyth, MJ, Engwerda, CR, MacDonald, KPA, Trapani, JA, Degli-Esposti, MA, Koyama, M & Hill, GR 2020, 'ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome', Cancer Immunology Research, vol. 8, no. 8, pp. 1085-1098. https://doi.org/10.1158/2326-6066.CIR-19-0653

TY - JOUR

T1 - ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

AU - Cheong, Melody

AU - Gartlan, Kate H.

AU - Lee, Jason S.

AU - Tey, Siok Keen

AU - Zhang, Ping

AU - Kuns, Rachel D.

AU - Andoniou, Christopher E.

AU - Martins, Jose Paulo

AU - Chang, Karshing

AU - Sutton, Vivien R.

AU - Kelly, Greg

AU - Varelias, Antiopi

AU - Vuckovic, Slavica

AU - Markey, Kate A.

AU - Boyle, Glen M.

AU - Smyth, Mark J.

AU - Engwerda, Christian R.

AU - MacDonald, Kelli P.A.

AU - Trapani, Joseph A.

AU - Degli-Esposti, Mariapia A.

AU - Koyama, Motoko

AU - Hill, Geoffrey R.

PY - 2020/8

Y1 - 2020/8

N2 - The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

AB - The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

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U2 - 10.1158/2326-6066.CIR-19-0653

DO - 10.1158/2326-6066.CIR-19-0653

M3 - Article

C2 - 32444423

AN - SCOPUS:85089126269

SN - 2326-6066

VL - 8

SP - 1085

EP - 1098

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 8

ER -

ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

Abstract

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