Suppression of pro-inflammatory T-cell responses by human mesothelial cells.
BACKGROUND
Human γδ T cells reactive to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD)-associated infections with HMB-PP producing bacteria are characterized by locally elevated γδ T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that γδ T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental γδ T-cell responses remains to be investigated.


METHODS
Freshly isolated γδ or αβ T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry.


RESULTS
Resting mesothelial cells were potent suppressors of pro-inflammatory γδ T cells as well as CD4+ and CD8+ αβ T cells. The suppression of γδ T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-β and activin signalling. Recombinant TGF-β1 but not activin-A mimicked the mesothelial cell-mediated suppression of γδ T-cell responses to HMB-PP.


CONCLUSIONS
The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation.
Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
Chan-Yu
CY
Lin
Ann
A
Kift-Morgan
Bernhard
B
Moser
Nicholas
N
Topley
Matthias
M
Eberl
D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D011756:Diphosphates / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D009852:Omentum / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010530:Peritoneal Dialysis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
C443995:4-hydroxy-3-methylbut-2-enyl pyrophosphate; D016207:Cytokines; D011756:Diphosphates; D018836:Inflammation Mediators; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016212:Transforming Growth Factor beta
TGF-β; inflammation; mesothelial cells; peritoneal dialysis; γδ T lymphocytes