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Help for cytotoxic-T-cell responses is mediated by CD40 signalling

Abstract

Cytotoxic T lymphocytes (CTLs) which carry the CD8 antigen recognize antigens that are presented on target cells by the class I major histocompatibility complex. CTLs are responsible for the killing of antigen-bearing target cells, such as virus-infected cells. Although CTL effectors can act alone when killing target cells, their differentiation from naive CD8-positive T cells is often dependent on ‘help’ from CD4-positive helper T (TH) cells1,2,3,4. Furthermore, for effective CTL priming, this help must be provided in a cognate manner, such that both the TH cell and the CTL recognize antigen on the same antigen-presenting cell2,4. One explanation for this requirement is that TH cells are needed to convert the antigen-presenting cell into a cell that is fully competent to prime CTL5. Here we show that signalling through CD40 on the antigen-presenting cells can replace the requirement for TH cells, indicating that T-cell ‘help’, at least for generation of CTLs by cross-priming, is mediated by signalling through CD40 on the antigen-presenting cell.

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Figure 1: OVA-specific CTLs can be generated in CD4-independent and CD4-dependent ways.
Figure 2: Treatment with a monoclonal antibody against CD40 replaces CD4-positive T-cell help in generating OVA-specific CTLs.
Figure 3: A CD40-specific monoclonal antibody can replace CD4-positive T-cell help in the induction of OVA-specific CTLs.
Figure 4: The role of CD154 and CD40 in the generation of OVA-specific CTLs by cross-priming.

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Acknowledgements

We thank H. Kikutani for the use of CD40-deficient mice; J. Ruby for providing these mice; A. Rolink for provision of the CD40-specific monoclonal antibody FGK145; D. Mathis for the use of class II deficient mice; J. Falso and T. Banjanin for technical assistance; and P. Matzinger, J. Ridge, and S. Schoenberger for helpful discussion. This work was supported by the Cooperative Research Centre for Vaccine Technology, and grants from the NIH, National Health and Medical Research Council, and Australian Research Council. R.A.F. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to William R. Heath.

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Bennett, S., Carbone, F., Karamalis, F. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998). https://doi.org/10.1038/30996

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