γδT Cells Exacerbate Podocyte Injury via the CD28/B7-1-Phosphor-SRC Kinase Pathway

Area of Science:

• Immunology
• Nephrology
• Molecular Biology

Background:

• Primary nephrotic syndrome (PNS) is a severe pediatric kidney disorder with unclear mechanisms.
• B7-1 expression in podocytes and the role of gamma delta (γδ) T cells in immune diseases are known.
• The potential interaction between γδT cells and podocytes via the CD28/B7-1 pathway in PNS is unexplored.

Purpose of the Study:

• To investigate if and how γδT cells impact podocytes through the CD28/B7-1 pathway in the context of nephrotic syndrome.
• To elucidate the molecular mechanisms underlying γδT cell-mediated podocyte injury.
• To evaluate the therapeutic potential of blocking the CD28/B7-1 pathway.

Main Methods:

• Utilized wild-type (WT) and TCRδ^-/- mice, with lipopolysaccharide (LPS) to induce nephropathy.
• Quantified γδT cells, CD28⁺γδT cells, B7-1, and phosphor-SRC levels in kidney and spleen.
• Performed in vitro co-culture of γδT cells with mouse podocytes, assessing apoptosis and phosphor-SRC expression, and tested CD28/B7-1 blockade using CTLA4-Ig.

Main Results:

• WT mice with LPS-induced nephropathy exhibited increased renal γδT cells and elevated B7-1 and phosphor-SRC levels.
• TCRδ^-/- mice showed alleviated kidney injury, while podocytes co-cultured with γδT cells displayed increased apoptosis and phosphor-SRC.
• CD28/B7-1 blockade with CTLA4-Ig in vitro significantly reduced podocyte injury.

Conclusions:

• γδT cells exacerbate podocyte injury in nephrotic syndrome via the CD28/B7-1 signaling pathway, involving downstream phosphor-SRC.
• The CD28/B7-1 pathway is a critical mediator of podocyte damage in this condition.
• CTLA4-Ig blockade of CD28/B7-1 presents a promising therapeutic strategy for primary nephrotic syndrome.