Serendipitous Discovery of T Cell-Produced KLK1b22 as a Regulator of Systemic Metabolism

Area of Science:

• Immunology
• Metabolic Research
• Molecular Biology

Background:

• The mechanistic/mammalian target of rapamycin (mTOR) pathway is crucial for T cell differentiation.
• Selective deletion of Rheb in T cells (T-Rheb-/-) in mice led to unexpected metabolic phenotypes.

Purpose of the Study:

• To investigate the role of Rheb in T cell differentiation and its impact on systemic metabolism.
• To identify novel factors involved in metabolic regulation originating from T cells.

Main Methods:

• Generated T-Rheb-/- mice on a C57BL/6J background.
• Performed microarray analysis on Rheb-/- T cells.
• Utilized in vitro overexpression systems and CRISPR-mediated knockout in mice.
• Queried the mouse Immunologic Genome Project database.

Main Results:

• T-Rheb-/- mice exhibited increased body weight, improved glucose tolerance, enhanced insulin sensitivity, and increased beige fat.
• Microarray analysis revealed significantly elevated kallikrein 1-related peptidase b22 (Klk1b22) expression in Rheb-/- T cells.
• Overexpression of Klk1b22 enhanced insulin receptor signaling in vitro and improved glucose tolerance in vivo.
• CRISPR-mediated knockout of Klk1b22 in 129S1/SVLMJ mice impaired glucose tolerance.
• Klk1b22 expression was found to be elevated in specific wild-type mouse strains with improved glucose tolerance.

Conclusions:

• T cell-derived Klk1b22 plays a novel and significant role in regulating systemic glucose metabolism and insulin sensitivity.
• The findings highlight a previously unrecognized link between T cell function and metabolic homeostasis.
• The observed metabolic benefits in T-Rheb-/- mice are attributed to Klk1b22, a finding independent of Rheb's direct role in T cell differentiation.