The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

Litjens, Nicolle H.R.; Wetering, Jacqueline van de; Besouw, Nicole M. van; Betjes, Michiel G. H.

doi:10.1182/blood-2009-03-211896

Cited by 31 publications

(32 citation statements)

References 34 publications

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“…+ T cells and CD154-expressing CD4 + T cells was made as we [13] and others [16,17] have previously described CD154 as a sensitive marker for detection of antigen-reactive CD4 + T cells. The CD154 assay has been described in detail previously [13,24].…”

Section: Cell-surface Expression Of Cd137 or Cd154 On Alloantigen-stimentioning

confidence: 99%

“…However, this method has gained little interest, as the very low frequency of cytokine + alloreactive T cells requires a skilled flow cytometry measurement resulting in low background signals [13]. If this is not applied it may lead to the erroneous conclusion that bs_bs_banner Clinical and Experimental Immunology ORIGINAL ARTICLE doi:10.1111/cei.12152 cytokine + alloreactive T cells cannot be detected in the peripheral blood [14].…”

Section: Introductionmentioning

confidence: 99%

“…We have adapted the CD154 live assay [16,17] and were able to identify alloreactive CD4 + T cells with great sensitivity and specificity in combination with phenotypic and functional analysis on the single-cell level [13]. The short-term culture period allows for a fast assay without significant changes in the phenotype of the T cell subsets.…”

Section: Introductionmentioning

confidence: 99%

“…However, CD154 is not expressed by alloreactive CD8 + T cells [13] and therefore the assay cannot be used to identify the total pool of alloreactive T cells. Cell surface expression of CD137, a member of the tumour necrosis factor receptor (TNFR) family, has been used successfully to identify antigen-reactive cells in both the CD4 + and CD8 + T cell compartments [18,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Litjens

Wit

Baan

et al. 2013

Clinical and Experimental Immunology

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SummaryDetection and isolation of viable alloreactive T cells at the single-cell level requires a cell surface marker induced specifically upon T cell receptor activation. In this study, a member of the tumour necrosis factor receptor (TNFR)-family, CD137 (4-1BB) was investigated for its potential to identify the total pool of circulating alloreactive T cells. Optimal conditions for sensitive and specific detection of allogeneic-induced CD137 expression on circulating T cells were established. Thereafter, CD137+ alloreactive T cells were phenotypically and functionally characterized by multi-parameter flow cytometry. Alloantigen-induced CD137 expression identified both alloreactive CD8 + T cells (mean ± standard error of the mean: 0·21 ± 0·07%) and alloreactive CD4 + T cells (0·21 ± 0·05%). CD137 + alloreactive T cells were detected in different T cell subsets, including naive T cells, but were found preferentially in CD28+ T cells and not in the terminally differentiated T cell subset. Upon allogeneic (re-)stimulation, the cytokine-producing as well as proliferative capacity of T cells resided mainly within the CD137-expressing fraction. About 10% of the CD137 + alloreactive T cells produced any combination of interferon (IFN)-γ, interleukin (IL)-2 and TNF-α. Polyfunctional alloreactive T cells, defined by multiple cytokine expression, were observed infrequently. In conclusion, activation-induced CD137 expression is a fast assay allowing for detection and functional analysis of the total alloreactive T cell compartment at the single-cell level by multiparameter flow cytometry.

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Section: Cell-surface Expression Of Cd137 or Cd154 On Alloantigen-stimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Litjens

Wit

Baan

et al. 2013

Clinical and Experimental Immunology

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“…PBMCs were isolated from healthy donor-derived buffy coats obtained from the local blood bank (Sanquin Blood Bank, Rotterdam, The Netherlands), as described previously in detail (32). This study did not require approval from an ethical committee according to the Dutch Medical Research Involving Human Subjects Act (WMO).…”

Section: Blood Samplesmentioning

confidence: 99%

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

Litjens

Boer

Zuijderwijk

et al. 2015

The Journal of Immunology

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Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4+CD25brightCD127− T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR– and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17–producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function.

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Donor Th17 cells and IL‐21 may contribute to the development of chronic graft‐versus‐host disease after allogeneic transplantation

Zhao

et al. 2013

Eur J Immunol

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Keywords: Chronic GVHD r HSCT r IL-21 r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered an effective treatment method for hematological malignancies, but graft-versus-host disease (GVHD) is a potentially lethal complication after allo-HSCT. Chronic GVHD (cGVHD) is not only a major cause of nonrelapse mortality but also induces substantial morbidity, which can severely affect the quality of life [1,2]. Despite improvements in the practice of allo-HSCT over the Correspondence: Prof. Xiao-Jun Huang e-mail: xjhrm@medmail.com.cn last 30 years, there has been little change in the incidence, morbidity, and mortality of cGVHD. One of the difficulties in combating cGVHD is the poor understanding of its pathogenesis [3].Chronic GVHD differs from acute GVHD (aGVHD) in many aspects. cGVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases, such as systemic lupus erythematosus, Sjögren's syndrome, lichen planus, and scleroderma. However, in contrast to aGVHD, it is unclear how autoimmune responses develop in cGVHD [3,4].IL-17-producing CD4 + T lymphocytes, named Th17 cells, play a crucial role in triggering inflammation and tissue injury in several autoimmune diseases [5]. Increasingly, the Th17 differentiation pathway has been shown to play important roles in aGVHD [6,7]. We previously demonstrated that IL-17-producing C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 838-850 Clinical immunology 839T cells contribute to aGVHD after allogeneic blood marrow transplantation [8]. However, the role of Th17 cells in cGVHD is controversial [7,[9][10][11]. Using the B10.D23→BALB/c cGVHD model, Nishimori et al. [9] show that cGVHD is significantly ameliorated in recipients of IL-17 −/− B10. D2 donor T cells compared with recipients of wild-type T cells, suggesting that Th17 cells contribute to cGVHD in this model. However, the (B6→BALB/c)→B6 Rag cGVHD model of Chen et al. [10] shows that cGVHD is not significantly ameliorated in recipients transplanted with IL-17 −/− B6 donor T cells, suggesting that IL-17 is not required for autoimmune-mediated pathologic damage during cGVHD. Furthermore, recent clinical data have also demonstrated contradictory roles for IL-17 as a central mediator of cGVHD pathology [7,11]. The work of Dander et al. [7] demonstrates an increased Th17-cell population in patients with cGVHD in addition to an inflammatory process. However, Ratajczak et al. [11] found that although skin-infiltrating Th17 cells can be identified by immunohistochemistry through IL-17A expression, the Th17/Treg-cell ratio is significantly lower than that observed in non-GVHD controls, which argues against a pathogenic role for the Th17 subset. Therefore, the role of Th17 cells in the pathogenesis of cGVHD must be further explored. Moreover, a recent study has shown that IL-21, one of the m...

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The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

Cited by 31 publications

References 34 publications

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

Donor Th17 cells and IL‐21 may contribute to the development of chronic graft‐versus‐host disease after allogeneic transplantation

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