Researchers at UCSF and CZ Biohub SF have described cells expressing a heterologous T-cell receptor, that binds to an adipose-specific protein perilipin 1 peptide complex, thereby enabling selecting targeting of fat cells.
T cell tolerance is enforced in the thymus through the expression of a wide array of self proteins called tissue-specific antigens (TSAs) which are under the control of the transcriptional regulator Autoimmune Regulator (Aire). CD4 T cells that strongly recognize these TSAs are eliminated from the repertoire, and loss of Aire function in humans leads to Autoimmune Polyglandular Syndrome Type I, a rare disorder characterized by multi-organ autoimmunity. Adipose tissue houses many immune cell types that are essential to immune homeostasis, notably adipose-resident Tregs that are distinct from their counterpart in secondary lymphoid organs and are essential for fat homeostasis. Acquired lipodystrophies are characterized by autoimmune-mediated loss of adipose tissue, including acquired generalized lipodystrophy (AGL) which involves extensive loss of subcutaneous fat from nearly all large regions of the body.
Stage of Research
The authors have discovered that a large fraction of the autoimmune response in patients with AGL is due to targeting by autoantibodies to an adipocyte-specific lipid droplet protein, perilipin 1 (PLIN1), which is involved in regulation of lipolysis and adipocyte homeostasis. Anti-PLIN1 antibodies were also found in a patient with lipodystrophy and autoimmune polyendocrine syndrome type I, establishing a link between loss of thymic tolerance and autoimmune attack on adipose tissue.
Applications
- Modifying fat cells in human subjects by introducing a cytotoxic T cell or a regulatory T-cell expressing a heterologous TCR that targets PLIN1 and reduces or regulates (i.e. increases) fat in the subject, respectively.
- Reduction of the autoimmune targeting of fat cells in a subject.
Advantages
- Selective targeting of fat cells for therapeutic purposes.
- Compatible with the autologous or allogenic administration of modified cells into humans or animals.
- Multiple routes of administration of molecules, vectors or cells are possible, including, but not limited to, parenteral or oral.
Stage of Development
Research – in vitro
Keywords
Autoimmune, autoantibody, therapeutic
Technology Reference:
CZ Biohub SF ref. no. CZB-320F-P1
UCSF ref. no. SF2025-062
