Cytotoxic T Lymphocytes Targeting a Conserved SARS-CoV-2 Spike Epitope are Efficient Serial Killers

Abstract

Understanding immune response to infections and vaccines lags understanding humoral responses. While neutralizing antibody responses wane over time, T cells are instrumental in long-term immunity. We apply machine learning and time-lapse imaging microscopy in nanowell grids (TIMING) to study thousands of videos of T cells with specificity for SARS-CoV-2 eliminating targets bearing spike protein as a surrogate for viral infection. The data on effector functions, including cytokine secretion and cytotoxicity, provide the first direct evidence that cytotoxic T lymphocytes from a convalescent patient targeting an epitope conserved across all known variants of concern are serial killers capable of eliminating multiple infected target cells. These data have implications for vaccine development and for the recovery and monitoring of infected individuals.

Cytotoxic T Lymphocytes Control Growth of B16 Tumor Cells in Collagen–Fibrin Gels by Cytolytic and Non-Lytic Mechanisms

“…The first insights came from generating conjugates between target cells and CTLs and quantifying how quickly a target cell dies when either being bound by a different number of CTLs or when one CTL binds to different targets [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Further in vitro studies highlighted that killing by CTLs may kill multiple targets rapidly [ 17 , 18 , 19 ], but also highlighted heterogeneity in the efficacy at which individual CTLs kill their targets [ 20 , 21 ]. Interestingly, killing of tumor cells in vitro may take a long time (hours) with speed and turning being important in determining the likelihood that a CTL will find and kill the target [ 22 , 23 ].…”

Mathematical modeling suggests cytotoxic T lymphocytes control growth of B16 tumor cells in collagin-fibrin gels by cytolytic and non-lytic mechanisms

“…First insights came from generating conjugates between target cells and CTLs and quantifying how quickly a target cell dies when either being bound by different number of CTLs, or when one CTL is bound to different targets [10][11][12][13][14][15][16][17]. Further in vitro studies highlighted that killing by CTLs may kill multiple targets rapidly [18][19][20] but also highlighted heterogeneity in efficacy at which individual CTLs kill their targets [21,22]. Interestingly, killing of tumor cells in vitro may take long time (hours) with speed and turning being important in determining the likelihood that a CTL will find and kill the target [23,24].…”