title: Dissociating markers of senescence and protective ability in memory T cells.
abstract: No unique transcription factor or biomarker has been identified to reliably distinguish effector from memory T cells. Instead a set of surface markers including IL-7Rα and KLRG1 is commonly used to predict the potential of CD8 effector T cells to differentiate into memory cells. Similarly, these surface markers together with the tumor necrosis factor family member CD27 are frequently used to predict a memory T cell's ability to mount a recall response. Expression of these markers changes every time a memory cell is stimulated and repeated stimulation can lead to T cell senescence and loss of memory T cell responsiveness. This is a concern for prime-boost vaccine strategies which repeatedly stimulate T cells with the aim of increasing memory T cell frequency. The molecular cues that cause senescence are still unknown, but cell division history is likely to play a major role. We sought to dissect the roles of inflammation and cell division history in developing T cell senescence and their impact on the expression pattern of commonly used markers of senescence. We developed a system that allows priming of CD8 T cells with minimal inflammation and without acquisition of maximal effector function, such as granzyme expression, but a cell division history similar to priming with systemic inflammation. Memory cells derived from minimal effector T cells are fully functional upon rechallenge, have full access to non-lymphoid tissue and appear to be less senescent by phenotype upon rechallenge. However, we report here that these currently used biomarkers to measure senescence do not predict proliferative potential or protective ability, but merely reflect initial priming conditions.
authors.affiliation: Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, United States of America. mprlic@fhcrc.org
authors.forename: Martin
authors.initials: M
authors.lastname: Prlic
authors.forename: Jilian A
authors.initials: JA
authors.lastname: Sacks
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bevan
mesh_terms: D000818:Animals; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002455:Cell Division; D002469:Cell Separation; D016922:Cellular Senescence; D003713:Dendritic Cells / Q000166:cytology; D005434:Flow Cytometry / Q000379:methods; D053804:Granzymes / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory; D007249:Inflammation; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D018960:Hyaluronan Receptors; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D020395:Receptors, Interleukin-7; D015534:Trans-Activators; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C415350:interleukin-7 receptor, alpha chain; D053804:Granzymes