Antigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cells

TY - JOUR

T1 - Antigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cells

AU - Linke, Alexandra

AU - Cicek, Hakan

AU - Müller, Anne

AU - Meyer-Schwesinger, Catherine

AU - Melderis, Simon

AU - Wiech, Thorsten

AU - Wegscheid, Claudia

AU - Ridder, Julius

AU - Steinmetz, Oliver M

AU - Diehl, Linda

AU - Tiegs, Gisa

AU - Neumann, Katrin

PY - 2022/4/30

Y1 - 2022/4/30

N2 - Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ T-cell activation. Whether PTECs have the potential to induce activation of CD8+ T cells is less clear. In this study, we aimed to investigate the capacity of PTECs for antigen cross-presentation thereby modulating CD8+ T-cell responses. We showed that PTECs expressed proteins associated with cross-presentation, internalized soluble antigen via mannose receptor-mediated endocytosis, and generated antigenic peptides by proteasomal degradation. PTECs induced an antigen-dependent CD8+ T-cell activation in the presence of soluble antigen in vitro. PTEC-activated CD8+ T cells expressed granzyme B, and exerted a cytotoxic function by killing target cells. In murine lupus nephritis, CD8+ T cells localized in close contact to proximal tubuli. We determined enhanced apoptosis in tubular cells and particularly PTECs up-regulated expression of cleaved caspase-3. Interestingly, induction of apoptosis in the inflamed kidney was reduced in the absence of CD8+ T cells. Thus, PTECs have the capacity for antigen cross-presentation thereby inducing cytotoxic CD8+ T cells in vitro, which may contribute to the pathology of immune-mediated glomerulonephritis.

AB - Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ T-cell activation. Whether PTECs have the potential to induce activation of CD8+ T cells is less clear. In this study, we aimed to investigate the capacity of PTECs for antigen cross-presentation thereby modulating CD8+ T-cell responses. We showed that PTECs expressed proteins associated with cross-presentation, internalized soluble antigen via mannose receptor-mediated endocytosis, and generated antigenic peptides by proteasomal degradation. PTECs induced an antigen-dependent CD8+ T-cell activation in the presence of soluble antigen in vitro. PTEC-activated CD8+ T cells expressed granzyme B, and exerted a cytotoxic function by killing target cells. In murine lupus nephritis, CD8+ T cells localized in close contact to proximal tubuli. We determined enhanced apoptosis in tubular cells and particularly PTECs up-regulated expression of cleaved caspase-3. Interestingly, induction of apoptosis in the inflamed kidney was reduced in the absence of CD8+ T cells. Thus, PTECs have the capacity for antigen cross-presentation thereby inducing cytotoxic CD8+ T cells in vitro, which may contribute to the pathology of immune-mediated glomerulonephritis.

KW - Animals

KW - Antigen Presentation

KW - CD8-Positive T-Lymphocytes

KW - Cross-Priming

KW - Epithelial Cells/metabolism

KW - Kidney Tubules, Proximal/metabolism

KW - Mice

U2 - 10.3390/cells11091510

DO - 10.3390/cells11091510

M3 - SCORING: Journal article

C2 - 35563816

VL - 11

JO - CELLS-BASEL

JF - CELLS-BASEL

SN - 2073-4409

IS - 9

M1 - 1510

ER -