Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients

Aafke A. Duizendstra; Robert J. de Knegt; Shanta Mancham; Mariska Klepper; Dave L. Roelen; Simone H. Brand-Schaaf; Patrick P. Boor; Michail Doukas; Robert A. de Man; Dave Sprengers; Maikel P. Peppelenbosch; Michiel G.H. Betjes; Jaap Kwekkeboom; Nicolle H.R. Litjens

doi:10.1002/lt.26188

Activated CD4⁺ T Cells and Highly Differentiated Alloreactive CD4⁺ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients

Aafke A. Duizendstra, Robert J. de Knegt, Shanta Mancham, Mariska Klepper, Dave L. Roelen, Simone H. Brand-Schaaf, Patrick P. Boor, Michail Doukas, Robert A. de Man, Dave Sprengers, Maikel P. Peppelenbosch, Michiel G.H. Betjes, Jaap Kwekkeboom^*, Nicolle H.R. Litjens

^*Corresponding author for this work

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

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Abstract

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

Original language	English
Pages (from-to)	98-112
Number of pages	15
Journal	Liver Transplantation
Volume	28
Issue number	1
Early online date	3 Jun 2021
DOIs	https://doi.org/10.1002/lt.26188
Publication status	Published - Jan 2022

Bibliographical note

Acknowledgments:
We express our gratitude to the liver transplantation nurses of the Department of Gastroenterology and Hepatology at the Erasmus University Medical Centre for their efforts to successfully collect all heparinized blood samples. We also thank the Department of Viroscience at the Erasmus University Medical Centre for making archived serum samples of LT recipients available and for determination of CMV IgG serostatus.

Publisher Copyright:
Copyright © 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

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Duizendstra, A. A., de Knegt, R. J., Mancham, S., Klepper, M., Roelen, D. L., Brand-Schaaf, S. H., Boor, P. P., Doukas, M., de Man, R. A., Sprengers, D., Peppelenbosch, M. P., Betjes, M. G. H., Kwekkeboom, J., & Litjens, N. H. R. (2022). Activated CD4⁺ T Cells and Highly Differentiated Alloreactive CD4⁺ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients. Liver Transplantation, 28(1), 98-112. Advance online publication. https://doi.org/10.1002/lt.26188

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title = "Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients",

abstract = "Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.",

author = "Duizendstra, {Aafke A.} and {de Knegt}, {Robert J.} and Shanta Mancham and Mariska Klepper and Roelen, {Dave L.} and Brand-Schaaf, {Simone H.} and Boor, {Patrick P.} and Michail Doukas and {de Man}, {Robert A.} and Dave Sprengers and Peppelenbosch, {Maikel P.} and Betjes, {Michiel G.H.} and Jaap Kwekkeboom and Litjens, {Nicolle H.R.}",

note = "Acknowledgments: We express our gratitude to the liver transplantation nurses of the Department of Gastroenterology and Hepatology at the Erasmus University Medical Centre for their efforts to successfully collect all heparinized blood samples. We also thank the Department of Viroscience at the Erasmus University Medical Centre for making archived serum samples of LT recipients available and for determination of CMV IgG serostatus. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.",

year = "2022",

month = jan,

doi = "10.1002/lt.26188",

language = "English",

volume = "28",

pages = "98--112",

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Duizendstra, AA, de Knegt, RJ , Mancham, S , Klepper, M, Roelen, DL, Brand-Schaaf, SH, Boor, PP, Doukas, M , de Man, RA , Sprengers, D , Peppelenbosch, MP , Betjes, MGH, Kwekkeboom, J & Litjens, NHR 2022, 'Activated CD4⁺ T Cells and Highly Differentiated Alloreactive CD4⁺ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients', Liver Transplantation, vol. 28, no. 1, pp. 98-112. https://doi.org/10.1002/lt.26188

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T1 - Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients

AU - Duizendstra, Aafke A.

AU - de Knegt, Robert J.

AU - Mancham, Shanta

AU - Klepper, Mariska

AU - Roelen, Dave L.

AU - Brand-Schaaf, Simone H.

AU - Boor, Patrick P.

AU - Doukas, Michail

AU - de Man, Robert A.

AU - Sprengers, Dave

AU - Peppelenbosch, Maikel P.

AU - Betjes, Michiel G.H.

AU - Kwekkeboom, Jaap

AU - Litjens, Nicolle H.R.

N1 - Acknowledgments: We express our gratitude to the liver transplantation nurses of the Department of Gastroenterology and Hepatology at the Erasmus University Medical Centre for their efforts to successfully collect all heparinized blood samples. We also thank the Department of Viroscience at the Erasmus University Medical Centre for making archived serum samples of LT recipients available and for determination of CMV IgG serostatus. Publisher Copyright: Copyright © 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

PY - 2022/1

Y1 - 2022/1

N2 - Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

AB - Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation-induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third-party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor-specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

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Activated CD4⁺ T Cells and Highly Differentiated Alloreactive CD4⁺ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients

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