JCI Insight. 2023 Aug 15. pii: e169308. [Epub ahead of print]
Aya G Elmarsafawi,
Rebecca S Hesterberg,
Mario R Fernandez,
Chunying Yang,
Lancia Nf Darville,
Min Liu,
John M Koomen,
Otto Phanstiel Iv,
Reginald Atkins,
John E Mullinax,
Shari A Pilon-Thomas,
Frederick L Locke,
Pearlie K Epling-Burnette,
John L Cleveland.
Glutaminolysis is a hallmark of the activation and metabolic reprogramming of T cells. Isotopic tracer analyses of antigen-activated effector CD8+ T cells revealed that glutamine is the principal carbon source for the biosynthesis of polyamines putrescine, spermidine and spermine. These metabolites play critical roles in activation-induced T-cell proliferation, as well as for the production of hypusine, which is derived from spermidine and is covalently linked to the translation elongation factor eIF5A. Here, we demonstrated that the glutamine-polyamine-hypusine axis controls the expression of CD69, an important regulator of tissue resident memory T cells (TRM). Inhibition of this circuit augmented the development of TRM cells ex vivo and in vivo in the bone marrow, a well-established niche for TRM cells. Furthermore, blocking the polyamine-hypusine axis augmented CD69 expression and IFN-γ and TNF-α production in human CD8+ T cells from peripheral blood and sarcoma tumor infiltrating lymphocytes, as well as in human CD8+ CAR-T cells. Collectively, these findings support the notion that the polyamine-hypusine circuit can be exploited to modulate TRM cells for therapeutic benefit.
Keywords: Immunology; Metabolism; Polyamines; T cells