T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention

Jamie van Langelaar, Roos M. van der Vuurst de Vries, Malou Janssen, Annet F. Wierenga-Wolf, Isis M. Spilt, Theodora A. Siepman, Wendy Dankers, Georges M. G. M. Verjans, Helga E. de Vries, Erik Lubberts, Rogier Q. Hintzen, Marvin M. van Luijn

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

Interleukin-17-expressing CD4 + T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6 + CXCR3 +), and not Th17 (CCR6 + CXCR3 -) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6 + and CCR6 - CD8 + T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6 + CXCR3 + CCR4 -) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.
Original languageEnglish
Pages (from-to)1334-1349
JournalBrain
Volume141
Issue number5
DOIs
Publication statusPublished - 2018

Cite this

van Langelaar, J., van der Vuurst de Vries, R. M., Janssen, M., Wierenga-Wolf, A. F., Spilt, I. M., Siepman, T. A., ... van Luijn, M. M. (2018). T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention. Brain, 141(5), 1334-1349. https://doi.org/10.1093/brain/awy069
van Langelaar, Jamie ; van der Vuurst de Vries, Roos M. ; Janssen, Malou ; Wierenga-Wolf, Annet F. ; Spilt, Isis M. ; Siepman, Theodora A. ; Dankers, Wendy ; Verjans, Georges M. G. M. ; de Vries, Helga E. ; Lubberts, Erik ; Hintzen, Rogier Q. ; van Luijn, Marvin M. / T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention. In: Brain. 2018 ; Vol. 141, No. 5. pp. 1334-1349.
@article{1840a4e8e16e429785f560c6acb4efbe,
title = "T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention",
abstract = "Interleukin-17-expressing CD4 + T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6 + CXCR3 +), and not Th17 (CCR6 + CXCR3 -) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6 + and CCR6 - CD8 + T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6 + CXCR3 + CCR4 -) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.",
author = "{van Langelaar}, Jamie and {van der Vuurst de Vries}, {Roos M.} and Malou Janssen and Wierenga-Wolf, {Annet F.} and Spilt, {Isis M.} and Siepman, {Theodora A.} and Wendy Dankers and Verjans, {Georges M. G. M.} and {de Vries}, {Helga E.} and Erik Lubberts and Hintzen, {Rogier Q.} and {van Luijn}, {Marvin M.}",
year = "2018",
doi = "10.1093/brain/awy069",
language = "English",
volume = "141",
pages = "1334--1349",
journal = "Brain",
issn = "0006-8950",
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van Langelaar, J, van der Vuurst de Vries, RM, Janssen, M, Wierenga-Wolf, AF, Spilt, IM, Siepman, TA, Dankers, W, Verjans, GMGM, de Vries, HE, Lubberts, E, Hintzen, RQ & van Luijn, MM 2018, 'T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention' Brain, vol. 141, no. 5, pp. 1334-1349. https://doi.org/10.1093/brain/awy069

T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention. / van Langelaar, Jamie; van der Vuurst de Vries, Roos M.; Janssen, Malou; Wierenga-Wolf, Annet F.; Spilt, Isis M.; Siepman, Theodora A.; Dankers, Wendy; Verjans, Georges M. G. M.; de Vries, Helga E.; Lubberts, Erik; Hintzen, Rogier Q.; van Luijn, Marvin M.

In: Brain, Vol. 141, No. 5, 2018, p. 1334-1349.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention

AU - van Langelaar, Jamie

AU - van der Vuurst de Vries, Roos M.

AU - Janssen, Malou

AU - Wierenga-Wolf, Annet F.

AU - Spilt, Isis M.

AU - Siepman, Theodora A.

AU - Dankers, Wendy

AU - Verjans, Georges M. G. M.

AU - de Vries, Helga E.

AU - Lubberts, Erik

AU - Hintzen, Rogier Q.

AU - van Luijn, Marvin M.

PY - 2018

Y1 - 2018

N2 - Interleukin-17-expressing CD4 + T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6 + CXCR3 +), and not Th17 (CCR6 + CXCR3 -) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6 + and CCR6 - CD8 + T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6 + CXCR3 + CCR4 -) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

AB - Interleukin-17-expressing CD4 + T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6 + CXCR3 +), and not Th17 (CCR6 + CXCR3 -) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6 + and CCR6 - CD8 + T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6 + CXCR3 + CCR4 -) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

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van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA et al. T helper 17.1 cells associate with multiple sclerosis disease activity: Perspectives for early intervention. Brain. 2018;141(5):1334-1349. https://doi.org/10.1093/brain/awy069