Abstract
The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR–pMHC–CD8 trimolecular ‘catch bonds’, whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR–pMHC and pMHC–CD8 bimolecular ‘slip bonds’. Catch bonds were not intrinsic to either the TCR–pMHC or the pMHC–CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC–CD8 interaction to the intracellular interaction of CD8 with TCR–CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans–cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank L. Lawrence for maintaining the mouse colonies; L. Doudy for thymocyte purification; W. Chen and Z. Li for assistance with experiments and discussions; and the NIH Tetramer Core Facility at Emory University for providing the pMHC monomers. This work was supported by NIH grants CA214354 and AI124680 (to C.Z.), and NS071518 and AI096879 (to B.D.E.).
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Contributions
J.H., C.G., K.S., B.D.E., A.S., and C.Z. designed experiments; J.H., C.G., P.J., Z.Y., B.L., K.B., and K.L. performed experiments; Y.Z. and K.S. provided DNA force probes; M.S. and A.S. provided the OT1.CD8.4 mice; A.P. and P.L. provided the OT1.6F mice; W.R. performed modeling analysis; C.G., Z.Y., and X.Y. performed statistical analyses; and J.H. and C.Z. analyzed the data and wrote the paper, to which other authors contributed.
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Integrated supplementary information
Supplementary Figure 1 Lck inhibition eliminated trimolecular bonds of CD8.4 thymocytes with wQ4H7 but not with wQ4R7.
Related to Fig. 2. Molecular stiffness histograms of complexes of DMSO-treated OT1 (first column), Lck inhibitor-treated OT1.CD8.4 (second column) and DMSO-treated OT1.CD8.4 (third column) thymocytes with wQ4H7 (upper row) or wQ4R7 (bottom row). Data (bar) were fitted by a single or double Gaussian per panel. The fitting parameters and statistics for their comparisons are summarized in Supplementary Tables 4a, b and 5a, respectively.
Supplementary Figure 2 Further confirmation of the thymocyte negative-selection criteria by force-dependent bond lifetimes, molecular stiffness, and cell pulling.
Related to Fig. 4. a, Mean ± s.e.m. of lifetime versus force plots of total bonds with indicated peptides presented by H2-Kb (green square and blue diamond) or H2-Kbm3 (red square), TCR bonds with three peptides presented by H2-Kbα3A2 (brown circle), and CD8 bond with VSV:H-2Kb (black triangle) measured using 2C TCR transgenic mice. The total bonds with the negative selecting ligands, SIYR:H-2Kb and dEV8:H-2Kbm3, exhibited catch bond behavior at low forces whereas those with the positive selecting ligands, dEV8, EVSV and p2Ca bound to H-2Kb, showed slip bond behavior9–11,52. Like mOVA, the super agonist SIYR also formed catch bond at low forces with the 2C TCR in the absence of CD8, but the other two pMHC bimolecular interactions and the MHC–CD8 interaction formed slip bonds. The numbers of bond lifetime measurements per curve for different ligands, the results of statistical tests examining the trends of the curves and their differences are summarized in Supplementary Tables 1d, 2c and 3a,b, respectively. b, Molecular stiffness histograms of 2C TCR bimolecular complexes with the indicated peptides bound to H-2Kbα3A2, total complexes with these peptides bound to H-2Kb, and total complexes with dEV8:H-2Kbm3 and p2Ca:H-2Kb. Data (bar) were fitted by a single (black curve) or double (black curve = cyan curve + red curve) Gaussian. The fitting parameters and statistics for their comparisons are summarized in Supplementary Tables 4c and 5c, respectively. c, Representative images of thymocytes placed on wVSV, wCatnb, and wOVA tagged with a 13.1 pN MTP viewed in the bright-field (left column), fluorescence (middle column), and merged (right column) channels. Scale bar = 5 µm. d, Comparison of initial force signals from wVSV, wCatnb, and wOVA tagged with a 13.1 pN MTP. e, Comparison of force signal decays of OT1 thymocytes pulled on mOVA and wOVA tagged with a 13.1 pN MTP. f, Representative images of thymocytes pulled on indicated peptides presented by H-2Kb tagged with a 4.7 pN MTP viewed in the bright-field (left column), fluorescence (middle column), and merged (right column) channels. Scale bar = 5 µm. g, Comparison of normalized fluorescence intensity (points, left ordinate) and fraction of positive cells (bars, right ordinate) for indicated peptides bound to H2-Kb. Normalized fluorescence intensity was calculated by dividing the mean fluorescence intensity from a Cy5 positive cell by the background. Data are presented as mean ± s.e.m of all positive cells (each cell is represented by a point with N indicating the number of positive cells). h, Comparison of force signal decays of OT1 thymocytes pulled on wQ4H7 and wQ4R7 tagged by a 4.7 pN MTP. i, Representative images of OT1 thymocytes pulled on wOVA tagged with a 13.1 pN MTP treated with the indicated agents: DMSO control, actin polymerization inhibitor latruculin A, and ROCK inhibitor Y-27632. OT1 thymocytes before (top row) and 10 min after (bottom row) the drug treatment were viewed in the bright-field (left column), fluorescence (middle column), and merged (right column) channels. Scale bar = 5 µm. j, Comparison of force signal decays of OT1 thymcoytes pulled on wOVA over 20 min for the same treatments as in (i). Data in (e,h,j) are presented as mean ± s.e.m. of fluorescence intensity normalized by the initial value at 0 min (N = number of cells pooled from ≥at least two independent experiments). *and **** denote p < 0.05 and 0.0001, respectively, by two-way ANOVA.
Supplementary Figure 3 2D binding at zero force does not provide clear criteria for thymocyte negative selection.
Related to Fig. 5. a, Lifetimes of OT1 TCR bimolecular bonds with the indicated peptides bound to H2-Kbα3A2 or of the MHC–CD8 bond (wVSV) were measured by the BFP thermal fluctuation assay24 at zero-force. Their survival probabilities were plotted as fraction of events with a lifetime ≥ tb vs. lifetime tb. The number of bond lifetime measurements are: N = 52 (OVA), 39 (Q4), 49 (Q4R7), 26 (T4), 31 (Q4H7), 39 (Q7), 52 (G4), and 20 (VSV). b, Micrographs of the micropipette adhesion frequency assay25. A DP thymocyte (right) aspirated by a pipette was aligned with a RBC held by another pipette (left). The two cells were brought into a controlled contact for a given area (Ac) and duration (tc) and then retracted to detect binding, which was observed by the absence (top, no adhesion) or presence (bottom, adhesion) of RBC elongation. Scale bar = 5 µm. c, Specificity control. At 5 s contact, thymocytes adhered to RBCs coated with wOVA (13 μm-2) at higher frequency than those with mOVA (13 μm-2), showing the contribution of CD8 binding, but did not adhere to unmodified RBCs, biotinylated RBCs, and RBCs coated with biotin–SA (4335 μm-2) or mVSV (604 μm-2). Data are presented as mean ± s.e.m. of cell pairs each contacted 50 times to estimate an adhesion frequency. The number of cell pairs are: N = 3 (unmodified), 3 (biotin), 4 (biotin-SA), 3 (mVSV), 4 (mOVA), and 5 (wOVA). d, Adhesion frequency Pa vs. contact duration tc plots for indicated peptides bound to H2-Kbα3A2 (brown circle) or H2-Kb in the absence (blue square) or presence of anti-CD8 CT-CD8a (green triangle) or anti-TCR B20.1 (red diamond). Except for OVA whose measurements required a lower pMHC density (14-46 μm-2), a narrow range of pMHC densities (84-240 μm-2) were used to compare DP thymocyte adhesions in indicated conditions for each ligand. MHC–CD8 interaction (measured by using B20.1 to block TCR binding) mediated lower but clearly measureable adhesion frequencies than the total pMHC interactions with TCR and/or CD8. The much lower adhesions mediated by TCR than CD8 result from the 10 times lower expression of TCR than CD8 on DP thymocytes; but TCR still has higher affinities for pMHC than CD8 (cf. panel e). Since TCR–pMHC interactions (measured by using H2-Kbα3A2 or CT-CD8a blocking to abolish CD8 binding) were nearly undetectable for these peptides with such low pMHC densities, higher ligand densities (840-3739 μm-2) were used to measure their effective 2D affinities, as shown in panel e. Data are presented as mean ± s.e.m. of N≥3 cell pairs for 50 touches each pair. The data are representatives from at least two independent experiments per curve. e, No significant differences (p>0.5, one-way ANOVA) were observed among effective 2D affinities AcKa of TCR for pMHCs of distinctive selection outcomes (left ordinate, open bar, mean ± s.e.m., N≥5). MHC–CD8 AcKa (left ordinate, hatched bar, mean ± s.e.m., N=5) and available 3D tetramer values (right ordinate, black bar)4 are shown for comparison. f, To directly compare different ligands, the adhesion frequency data were converted to average number of bonds by <n> = – ln(1 – Pa), normalized by dividing them by the corresponding pMHC density mpMHC, and plotted versus contact duration tc. Except for OVA whose curve (red circle) is one log higher, the collapsed <ntotal>/mpMHC curves of the other ligands show no significant difference. The <nCD8>/mpMHC curve (black filled circle) is lower. g, Normalized total adhesion bonds, <ntotal>/mpMHC = – ln(1 – Pa)/mpMHC (open bar) for the indicated pMHCs (mean ± s.e.m., N≥3) and available 3D tetramer values (black bar)4 are shown for comparison. No significant differences were found among the middle 6 ligands (p>0.5, one-way ANOVA). The 2D kinetic parameters measured at zero force by adhesion frequency assay and thermal fluctuation assay are summarized in Supplementary Table 6
Supplementary Figure 4 Bond-lifetime distributions.
Related to Fig. 6. a,b, Survival probabilities of total OT1 TCR and/or CD8 bonds with the indicated peptides bound to H2-Kb (a) or bimolecular OT1 TCR bonds with the indicated peptides bound to H2-Kbα3A2 (b) measured by the force-clamp assay in the indicated force regimes. The MHC–CD8 interaction measured using VSV:H2-Kb is shown in black (a). c,d, Survival probabilities of total 2C TCR and/or CD8 bonds with the indicated peptides bound to H2-Kb or H-2Kbm3 (c) or bimolecular 2C TCR bonds with the indicated peptides bound to H2-Kbα3A2 (d) measured by the thermal fluctuation (0 pN) and force-clamp assay in the indicated force regimes. For the survival probabilities in (a-d), the higher the curve, the slower the dissociation, and the greater the number of bonds surviving a given time. The symbols and legend letters are color-coded to indicate thymocyte selection outcomes: red = negative selection, grey = selection threshold, and blue = positive selection. As force increases, the separation between red and blue curves increased, reached a maximum at 10-15 pN (third column), and then decreased. Separation in lifetime curves was greater for the total bonds that included the synergy between TCR and CD8 for pMHC binding (a, c) than bimolecular bonds between TCR and pMHC (b, d)
Supplementary Figure 5 Selection accuracy and ROC curves.
Related to Fig. 6. a, Selection accuracy SA versus threshold cumulative bond lifetime tth for a range of serial bond numbers n. b, SA versus n for a range tth at 0-5 pN with CD8 contribution, at 10-15 pN without CD8 contribution and at 0-5 pN without CD8 contribution. c, Receiver operating characteristic (ROC) curves plotting a thymocyte’s probability to be negatively selected by wQ4R7 (true-positive rate, or sensitivity) vs. its probability to be negatively selected by wQ4H7 (false-positive rate, or 1 - selectivity) for varying tth and a range of n. The three columns are calculated using the respective bond lifetime distributions of wQ4R7 and wQ4H7 at 0-5 pN, of mQ4R7 and mQ4H7 at 10-15 pN and of mQ4R7 and mQ4H7 at 0-5 pN from Supplementary Fig. 4a, b.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–5 and Supplementary Tables 1–6
Supplementary Video 1
Thymocytes exerting force on wQ4R7. Related to Figs. 3 and 4. Representative movie of a wild-type OT1 DP thymocyte pulling on wQ4R7. Thymocytes were placed on glass surfaces coated with wQ4R7 (tagged with a MTP with a force threshold of 13.1 pN) and anti-CD11a (not conjugated with any fluorescent dye). The de-quenched Cy5 signal indicates unfolding of the DNA hairpin by a >13.1 pN force generated by the thymocyte and applied to the pMHC via engaged TCR and CD8. Bright-field (left), Cy5 fluorescence (middle) and merged (right) images were recorded for 9 min.
Supplementary Video 2
Thymocytes exerting force on wQ4H7. Related to Figs. 3 and 4. Representative movie of a wild-type OT1 DP thymocyte pulling on wQ4H7. Thymocytes were placed on glass surfaces coated with wQ4H7 (tagged with a MTP with a force threshold of 13.1 pN) and anti-CD11a (not conjugated with any fluorescent dye). The de-quenched Cy5 signal indicates unfolding of the DNA hairpin by a >13.1 pN force generated by the thymocyte and applied to the pMHC via engaged TCR and CD8. Bright-field (left), Cy5 fluorescence (middle) and merged (right) images were recorded for 9 min.
Supplementary Video 3
3D images of a DP thymocytes pulling on wOVA. Related to Fig. 4. Rotating view of 3D reconstructed confocal images of a wild-type OT1 DP thymocyte placed on a glass surface, which was coated with wOVA (tagged with a MTP with a force threshold of 4.7 pN) and anti-CD11a (not conjugated with any fluorescent dye). The dequenched Cy5 signal indicates unfolding of the DNA hairpin by a >4.7 pN force generated by the thymocyte and applied to the pMHC via engaged TCR and CD8.
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Hong, J., Ge, C., Jothikumar, P. et al. A TCR mechanotransduction signaling loop induces negative selection in the thymus. Nat Immunol 19, 1379–1390 (2018). https://doi.org/10.1038/s41590-018-0259-z
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DOI: https://doi.org/10.1038/s41590-018-0259-z
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