TGF-beta treatment modulates PD-L1 and CD40 expression in proximal renal tubular epithelial cells and enhances CD8 cytotoxic T-cell responses.
OBJECTIVE
TGF-beta expression is increased in immune-mediated and fibrotic renal diseases and modulates the tubulointerstitial T-cell response. We examined whether TGF-beta changes the expression of PD-L1 and CD40 in the renal proximal tubular epithelial cell (TEC), and whether the activation of CD8(+) cytotoxic T cells (CTLs) is influenced by TGF-beta treatment of TECs.


METHODS
Murine TECs were treated with TGF-beta or IFN-gamma. The expression of PD-L1 and CD40 was examined with RT-PCR and flow cytometry. To investigate if TGF-beta treatment influenced the antigen presentation capacity of TECs, OT-1 CTLs were co-incubated with TGF-beta-treated, OVA(257-264) peptide-pulsed congeneic TECs. The cytotoxicity of OT-1 CTLs was estimated by their capacity to produce IFN-gamma and their cytolytic activity.


RESULTS
TGF-beta treatment lead to a transition in morphology of renal TECs and downregulated the basal and the IFN-gamma-stimulated PD-L1 expression in TECs. Interestingly, TGF-beta treatment of TECs increased the constitutive and IFN-gamma-induced CD40 expression. In contrast to IFN-gamma which reduced the CTL activity, TGF-beta treatment of TECs elevated the OVA-specific CTL response.


CONCLUSIONS
Our data show that TGF-beta changed the cellular phenotype and the expression of PD-L1 and CD40 on TECs and enhanced the activity of OVA peptide-specific CD8(+) T cells. TGF-beta may thereby play an important role in the progression of renal tubulointerstitial damage in CD8(+) T-cell-mediated renal diseases.
Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich-Irchel, Switzerland.
Astrid
A
Starke
Rudolf P
RP
Wüthrich
Ying
Y
Waeckerle-Men
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000939:Epitopes; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010047:Ovalbumin / Q000276:immunology*; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D019013:CD40 Antigens; C498919:Cd274 protein, mouse; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D010455:Peptides; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D010047:Ovalbumin