CXCR3 Identifies Human Naive CD8+ T Cells with Enhanced Effector Differentiation Potential

Gabriele De Simone(Humanitas University), Emilia Maria Cristina Mazza(Humanitas University), Antonino Cassotta(ETH Zurich), Alexey N. Davydov(Central European Institute of Technology), Mirela Kuka(Vita-Salute San Raffaele University), Veronica Zanon(Humanitas University), Fédérica De Paoli(Humanitas University), Eloise Scamardella(Humanitas University), Maria Metsger(Central European Institute of Technology), Alessandra Roberto(Humanitas University), Karolina Pilipow(Humanitas University), Federico Colombo(Humanitas University), Elena Tenedini(University of Modena and Reggio Emilia), Enrico Tagliafico(University of Modena and Reggio Emilia), Luca Gattinoni(University Hospital Regensburg), Domenico Mavilio(Humanitas University), Clelia Peano(Humanitas University), David A. Price(University of Wales Institute Cardiff), Satya P. Singh(National Institutes of Health), Joshua Μ. Farber(National Institutes of Health), Valentina Serra(Institute of Genetic and Biomedical Research), Francesco Cucca(Institute of Genetic and Biomedical Research), Francesco Ferrari(IFOM), Valeria Orrù(Institute of Genetic and Biomedical Research), Edoardo Fiorillo(Institute of Genetic and Biomedical Research), Matteo Iannacone(Vita-Salute San Raffaele University), Dmitriy M. Chudakov(Central European Institute of Technology), Federica Sallusto(ETH Zurich), Enrico Lugli(Humanitas University)
The Journal of Immunology
November 18, 2019
10.4049/jimmunol.1901072
Cited by 53Open Access
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Abstract

Abstract 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.

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