De Simone et al. identified two human naive CD8+ T cell subsets, CXCR3- (TNR3-) and more abundant CXCR3+ (TNR3+) cells, both residing in secondary lymphoid tissues and specific for self-derived antigens (Ag). Effector/memory and thymocyte differentiation genes are enriched in TNR3+ and TNR3- cells, respectively. In vitro, polyclonal activation of TNR3+, but not TNR3-, cells induced IL-2 and TNF, and Ag-stimulated TNR3+ cells made more perforin, IFNγ, and TNF than TNR3- cells. Inferences from β chain CDR3 sequences suggest stronger peptide-MHC-I contacts for TNR3+ versus TNR3- cells. Transcriptional parallelism was shown with murine (CD5hi) TNR3+ cells.
Contributed by Paula Hochman
In mice, the ability of naive T (TN) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8(+) TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3(+) TN cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3(+) TN cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3(+) TN cells were transcriptionally equivalent to murine CXCR3(+) TN cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8(+) T cells.
Author Info: (1) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (2) Laboratory of Translational Immunology, Humanitas Clinical and
Author Info: (1) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (2) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (3) Institute for Research in Biomedicine, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland. Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. (4) Central European Institute of Technology, 621 00 Brno, Czech Republic. (5) Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, 20132 Milan, Italy. (6) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (7) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (8) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (9) Central European Institute of Technology, 621 00 Brno, Czech Republic. (10) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (11) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (12) Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (13) Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. (14) Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy. (15) Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892. Regensburg Center for Interventional Immunology, University Regensburg and University Hospital Regensburg, 93053 Regensburg, Germany. (16) Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. Department of Medical Biotechnologies and Translational Medicine, University of Milan, 20122 Milan, Italy. (17) Division of Genetic and Biomedical Research, UoS Milan, National Research Council, 20089 Rozzano, Milan, Italy. Genomic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy. (18) Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom. Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom. (19) Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. (20) Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. (21) IRGB, National Research Council, 09042 Monserrato, Italy. (22) IRGB, National Research Council, 09042 Monserrato, Italy. (23) IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy. (24) IRGB, National Research Council, 09042 Monserrato, Italy. (25) IRGB, National Research Council, 09042 Monserrato, Italy. (26) Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, 20132 Milan, Italy. (27) Central European Institute of Technology, 621 00 Brno, Czech Republic. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia; and. Pirogov Russian National Research Medical University, 117997 Moscow, Russia. (28) Institute for Research in Biomedicine, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland. Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland. (29) Laboratory of Translational Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy; enrico.lugli@humanitasresearch.it. Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
