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T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions

Abstract

Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes1,2, the nature of the ‘help’ provided to CTLs is unknown3. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC)4. An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly5. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions6,7. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity8,9,10,11. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40–CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.

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Figure 1: Cross-priming of E1B-specific CTLs requires CD4+ T-helper cells.
Figure 2: CD40 activation replaces CD4+ helper T cells.
Figure 3: B cells are not essential as cross-priming APCs or for anti-CD40-mediated restoration of cross-priming.
Figure 4: CD40L blockade prevents cross-priming of E1B-specific CTLs.

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Acknowledgements

We thank P. Matzinger for discussions and for providing the B6I–Ab-knockout and µMT mice used in this study; A. Rolink for the FGK45 hybridoma; J. Laman for the purified MR1 antibody; and F. Ossendorp, F. Koning and R. De Vries for critically reading the manuscript and for making suggestions for its improvement. This work was funded by grants from the Dutch Cancer Society and the European Community. R.E.M.T. is a fellow of the Royal Dutch Academy of Arts and Sciences.

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Correspondence to Stephen P. Schoenberger.

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Schoenberger, S., Toes, R., van der Voort, E. et al. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998). https://doi.org/10.1038/31002

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