The Opposite Functions of CD30 Ligand Isoforms

TL;DR

This study reveals that a second isoform of CD30 ligand can block the signaling of the first isoform, which could impact treatments for cancer and inflammation.

Contribution

The study identifies and characterizes a previously unstudied CD30 ligand isoform with inhibitory properties.

Findings

Both CD30 ligand isoforms are expressed in PBMCs of healthy donors.

The second isoform lacks pro-inflammatory function and inhibits signaling of the canonical isoform.

This isoform can prevent interaction with the CD30 receptor, altering signaling outcomes.

Abstract

TNFSF8/CD30 ligand is a TNF superfamily member expressed on several major immune cell types, including activated monocytes, B, and T cells. The signaling of CD30 ligand through its cognate CD30 receptor has been shown to have effects on cell differentiation, cell death/survival, and cytokine production. The signaling pair has been implicated in hematopoietic malignancies and inflammatory disease, and a chemotherapy–CD30 antibody combination for the treatment of Hodgkin and other lymphomas has been developed. There are two recorded isoforms of CD30 ligand. All hitherto studies of CD30 ligand are of the first, canonical isoform, while the second isoform has never been described. This study aims to elucidate the properties and signaling functions of the second CD30 ligand isoform. We have found mRNA expression of both isoforms in the PBMCs of all six healthy donors tested. Through methods in cell biology and biochemistry, we were able to discover that the second CD30 ligand isoform has no discernable pro-inflammatory function and, in fact, isoform 2 can restrict the capacity of the canonical isoform to signal through the CD30 receptor by preventing their interaction. This discovery has implications for the future development of therapeutics targeting the CD30/CD30 ligand signaling pair in cancer and inflammatory disease.

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