Fig. 3: The CD4 co-receptor enhances the discrimination of helper cells expressing an MHC-I-restricted TCR.
a, Helper and cytotoxic T cells express the CD4 and CD8 co-receptors, respectively. b, Representative ligand discrimination assays using helper and cytotoxic c259 TCR-T cells recognizing peptides on U87 target cells. Expression of the 4-1BB activation marker was measured after a 20 h co-culture. c, P15 (mean ± s.d.) over TCR–pMHC affinity (KD) from N = 3 independent blood donors (points) is fitted to the kinetic proofreading model (solid line). d, Kinetic proofreading introduces a time delay (τKP) between pMHC binding (state C0) and TCR signalling (state CN) that selectively reduces signalling to low-affinity ligands. e, Fitted time delay from the data in c with 95% confidence interval. Two-tailed F-test compares the fitted proofreading time between conditions. f, Schematic of helper WT and CD4 KO c259 TCR-T cells. g, Flow cytometry staining of CD4 in WT and CD4 KO helper T cells. h, U87 cells were titrated with each of the 7 NY-ESO-1 peptides to stimulate WT or CD4 KO helper c259 TCR-T cells. 4-1BB expression was measured after 20 h. i, Fold change in potency (P15) between CD4 KO and WT helper T cells from h is plotted over TCR–pMHC affinity (KD). Dashed line indicates fold change of 1. Significance of non-zero slope was assessed using a two-tailed F-test. Data in b, g and h are representative of at least N = 3 independent experiments with different blood donors. Data in i are shown as mean ± s.d. of N = 5 independent experiments with different blood donors. **P < 0.01, ****P < 0.0001.
