title: Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization.
abstract: Inhibitory receptors mediate CD8 T-cell hyporesponsiveness against cancer and infectious diseases. PD-1 and CTLA-4 have been extensively studied, and blocking antibodies have already shown clinical benefit for cancer patients. Only little is known on extended co-expression of inhibitory receptors and their ligands. Here we analyzed the expression of eight inhibitory receptors by tumor-antigen specific CD8 T-cells. We found that the majority of effector T-cells simultaneously expressed four or more of the inhibitory receptors BTLA, TIM-3, LAG-3, KRLG-1, 2B4, CD160, PD-1 and CTLA-4. There were major differences depending on antigen-specificity, differentiation and anatomical localization of T-cells. On the other hand, naive T-cells were only single or double positive for BTLA and TIM-3. Extended co-expression is likely relevant for effector T-cells, as we found expression of multiple ligands in metastatic lesions of melanoma patients. Together, our data suggest that naive T-cells are primarily regulated by BTLA and TIM-3, whereas effector cells interact via larger numbers of inhibitory receptors. Blocking multiple inhibitory receptors simultaneously or sequentially may improve T-cell based therapies, but further studies are necessary to clarify the role of each receptor-ligand pair.
authors.affiliation: Clinical Tumor Biology and Immunotherapy Unit, Ludwig Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Baitsch
authors.forename: Amandine
authors.initials: A
authors.lastname: Legat
authors.forename: Leticia
authors.initials: L
authors.lastname: Barba
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Fuertes Marraco
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Rivals
authors.forename: Petra
authors.initials: P
authors.lastname: Baumgaertner
authors.forename: Céline
authors.initials: C
authors.lastname: Christiansen-Jucht
authors.forename: Hanifa
authors.initials: H
authors.lastname: Bouzourene
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Maurice
authors.initials: M
authors.lastname: Matter
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D019138:Antibodies, Blocking / Q000627:therapeutic use; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007155:Immunologic Factors; D008565:Membrane Proteins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011971:Receptors, Immunologic / Q000276:immunology; D054340:Receptors, KIR / Q000096:biosynthesis* / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; C482586:BTLA protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007155:Immunologic Factors; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR