Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness

Luisa Bopp; Maria Lopéz Martinez; Clara Schumacher; Robert Seitz; Manuel Huerta Arana; Henning Klapproth; Dominika Lukas; Ju Hee Oh; Daniela Neumayer; Jan W Lackmann; Stefan Mueller; Esther von Stebut; Bent Brachvogel; Susanne Brodesser; Ramon I Klein Geltink; Mario Fabri

doi:10.1016/j.isci.2024.109767

Glutamine promotes human CD8⁺ T cells and counteracts imiquimod-induced T cell hyporesponsiveness

iScience. 2024 Apr 18;27(5):109767. doi: 10.1016/j.isci.2024.109767. eCollection 2024 May 17.

Authors

Luisa Bopp¹, Maria Lopéz Martinez¹, Clara Schumacher¹, Robert Seitz¹, Manuel Huerta Arana¹, Henning Klapproth¹, Dominika Lukas¹, Ju Hee Oh^{2

3}, Daniela Neumayer¹, Jan W Lackmann⁴, Stefan Mueller⁵, Esther von Stebut¹, Bent Brachvogel^{5

6

7

8}, Susanne Brodesser⁸, Ramon I Klein Geltink^{2

3}, Mario Fabri^{1

5}

Affiliations

¹ Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine, and University Hospital of Cologne, Cologne, Germany.
² BC Children's Hospital Research Institute, Vancouver, BC, Canada.
³ University of British Columbia, Vancouver, BC, Canada.
⁴ CECAD Cluster of Excellence, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
⁵ Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
⁶ Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷ Center for Biochemistry, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸ University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Cologne, Germany.

Abstract

T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8⁺ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.

Keywords: Dermatology; Immunology.