Donor-derived IL-17A and IL-17F deficiency triggers Th1 allo-responses and increases gut leakage during acute GVHD
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Donor-derived IL-17A and IL-17F deficiency triggers Th1 allo-responses and increases gut leakage during acute GVHD. / Odak, Ivan; Depkat-Jakob, Alina; Beck, Maleen; Jarek, Michael; Yu, Yan; Seidler, Ursula; David, Sascha; Ganser, Arnold; Förster, Reinhold; Prinz, Immo; Koenecke, Christian.
in: PLOS ONE, Jahrgang 15, Nr. 4, e0231222, 2020.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Donor-derived IL-17A and IL-17F deficiency triggers Th1 allo-responses and increases gut leakage during acute GVHD
AU - Odak, Ivan
AU - Depkat-Jakob, Alina
AU - Beck, Maleen
AU - Jarek, Michael
AU - Yu, Yan
AU - Seidler, Ursula
AU - David, Sascha
AU - Ganser, Arnold
AU - Förster, Reinhold
AU - Prinz, Immo
AU - Koenecke, Christian
PY - 2020
Y1 - 2020
N2 - IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.
AB - IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.
KW - Animals
KW - Bone Marrow Transplantation
KW - CD4-Positive T-Lymphocytes/cytology
KW - Caco-2 Cells
KW - Cell Proliferation
KW - Gastrointestinal Microbiome
KW - Graft vs Host Disease/immunology
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Inflammation
KW - Interleukin-17/metabolism
KW - Intestines/immunology
KW - Macrophages/cytology
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Phenotype
KW - RNA, Ribosomal, 16S/metabolism
KW - Th1 Cells/cytology
U2 - 10.1371/journal.pone.0231222
DO - 10.1371/journal.pone.0231222
M3 - SCORING: Journal article
C2 - 32251446
VL - 15
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
M1 - e0231222
ER -