Understanding immune regulatory mechanisms of cytokines

Our laboratory investigates how cellular proteins regulate signal transduction, metabolic reactions, and organelle functions, and seeks to understand how dysfunction of these cellular events leads to the development of diseases in the immune and nervous systems.

Novel immune regulatory mechanisms of cytokines that are controlled by TRAF and TNF family molecules

The mammalian tumor necrosis factor receptor (TNFR)-associated factor (TRAF) is composed of seven family molecules numbered sequentially from TRAF1 to TRAF7. TRAF family molecules control the signaling activity of receptors for tumor necrosis factor-α (TNF-α), a representative pro-inflammatory cytokine, and related TNF family cytokines (Figure). Moreover, recent studies have demonstrated that TRAFs associate with immune receptors other than TNFRs and exhibit immune regulatory activities toward these unconventional receptors (Figure). However, the molecular mechanisms by which TRAFs regulate these receptors remain obscure.

TRAF5 was discovered as a signaling adaptor of several TNFR family molecules. CD4+ helper T cells help B cells to produce antibodies and play important roles in adaptive immunity. We have identified a novel attribute of TRAF5 in the receptor for interleukin-6 (IL-6), another pro-inflammatory cytokine critically involving CD4+ T cells. Furthermore, TRAF5 displays a regulatory role in Toll-like receptor signaling (Figure). We aim to understand novel and uncharacterized cellular functions of TRAF5 in the context of inflammation and immune-mediated diseases.

T cells express TNFR family molecules including OX40, 4-1BB, CD27, and GITR, whereas B cells express TNFRs such as CD40, BAFFR, TACI, and BCMA. These TNFRs regulate antigen-specific immune responses and play vital roles in the eradication of infections and cancers. We have prepared a range of recombinant TNF family proteins that bind to and stimulate cognate TNFRs expressed by T and B cells. We try to understand how to create TNF proteins that can generate beneficial immune responses.

Collectively, we aim to uncover uncharacterized immune regulatory mechanisms of cytokines to develop novel therapeutic strategies for immune-mediated diseases.

Molecular pathology of X-ALD

Dysfunction of peroxisomal ATP-binding cassette (ABC) protein subfamily D 1 (ABCD1) is responsible for X-linked adrenoleukodystrophy (X-ALD), which is characterized by inflammation in the cerebrum and progressive demyelination. We analyze the process of neurodegeneration in the brain that is driven by immune cells lacking expression of ABCD1.