Efficient discrimination between different densities of target antigen by tetracycline-regulatable T bodies.
Engineered T cells expressing chimeric T cell receptors (chTCRs) are of interest for cancer gene therapy but many "cancer antigens" are thought to be unsuitable targets because they are expressed at low levels on normal tissues. We therefore sought to determine whether engineered T cells expressing variable surface densities of a high-affinity chTCR could discriminate different concentrations of the targeted antigen. We plotted the relationship between chTCR density and the concentration of target antigen using Jurkat T cells expressing a hapten-binding chTCR whose expression could be modulated by tetracycline. Our analysis reveals that there is a dynamic equilibrium between cell surface density of the chTCR and the antigen density that optimally triggers T cell activation. At a fixed density of target antigen, optimal T cell activation can be achieved only within a certain range of chTCR densities, while excessive TCR signaling triggers apoptosis of the engineered T cells. Our results show that T cells can be engineered to discriminate different antigen densities and that the T cell response to a fixed concentration of antigen can be optimized by tuning the cell surface density of TCRs.
Alvarez-Vallina
L
L
Centre for Protein Engineering, MRC Centre, Cambridge, UK. lav@inmuno.cph.es
Russell
S J
SJ
D000951:Antigens, Neoplasm / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013752:Tetracycline / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D013752:Tetracycline