Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation, antigen-specificity and anatomical localization

PLoS One. 2012;7(2):e30852. doi: 10.1371/journal.pone.0030852. Epub 2012 Feb 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Blocking / therapeutic use
  • Antigens, Neoplasm
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology*
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immunologic Factors
  • Membrane Proteins / immunology
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Receptors, Immunologic / immunology
  • Receptors, KIR / biosynthesis*
  • Receptors, KIR / immunology
  • T-Cell Antigen Receptor Specificity / immunology*


  • Antibodies, Blocking
  • Antigens, Neoplasm
  • BTLA protein, human
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Immunologic Factors
  • Membrane Proteins
  • Receptors, Immunologic
  • Receptors, KIR