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Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity

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Abstract

Background

Alloreactive T-cell responses are known to result in the production of large amounts of proinflammatory cytokines capable of activating and maturing dendritic cells (DC). However, it is unclear whether these allogeneic responses could also act as an adjuvant for concurrent antigen-specific responses.

Objective

To examine effects of simultaneous alloreactive and antigen-specific T-cell responses induced by semi-allogeneic DC.

Methods

Semi-allogeneic DC were generated from the F1 progeny of inbred strains of mice (C57BL/6 and C3H, or C57BL/6 and DBA). We directly primed antigen-specific CD8+ and CD4+ T-cells from OT-I and OT-II mice, respectively, in the absence of allogeneic responses, in vitro, and in the presence or absence of alloreactivity in vivo.

Results

In vitro, semi-allogeneic DC cross-presented ovalbumin (OVA) to naïve CD8+ OT-I transgenic T-cells, primed naïve CD4+ OT-II transgenic T-cells and could stimulate strong alloreactive T-cell proliferation in a primary mixed lymphocyte reaction (MLR). In vivo, semi-allogeneic DC migrated efficiently to regional lymph nodes but did not survive there as long as autologous DC. In addition, they were not able to induce cytotoxic T-lymphocyte (CTL) activity to a target peptide, and only weakly stimulated adoptively transferred OT-II cells. The CD4+ response was unchanged in allo-tolerized mice, indicating that alloreactive T-cell responses could not provide help for concurrently activated antigen-specific responses. In an EL4 tumour-treatment model, vaccination with semi-allogeneic DC/EL4 fusion hybrids, but not allogeneic DC/EL4 hybrids, significantly increased mouse survival.

Conclusion

Expression of self-Major histocompatibility complex (MHC) by semi-allogeneic DC can cause the induction of antigen-specific immunity, however, concurrently activated allogeneic bystander responses do not provide helper or adjuvant effects.

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Abbreviations

51Cr:

51Chromium

CFSE:

Carboxy fluorescein succinimidyl ester

CTL:

Cytotoxic T-lymphocyte

DC:

Dendritic cell

ES:

Embryonic stem cells

MHC:

Major histocompatibility complex

MLR:

Mixed lymphocyte reaction

OVA:

Ovalbumin

SEM:

Standard error of the mean

TCR:

T-cell receptor

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Acknowledgements

This work was supported by Leukaemia Research Fund and a JRC studentship from King’s College London School of Medicine.

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Authors and Affiliations

  1. Department of Haematological and Molecular Medicine, King’s College London, The Rayne Institute, London, SE5 9NU, UK

    James W. Wells, David Darling, Barbara-Ann Guinn, Farzin Farzaneh & Joanna Galea-Lauri

  2. MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, 5th Floor Thomas Guy House, Guy’s Hospital, London, SE1 9RT, UK

    James W. Wells, Chris J. Cowled & Alistair Noble

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  1. James W. Wells
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Correspondence to Alistair Noble.

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Joanna Galea-Lauri and Alistair Noble share senior authorship of this work.

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Wells, J.W., Cowled, C.J., Darling, D. et al. Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity. Cancer Immunol Immunother 56, 1861–1873 (2007). https://doi.org/10.1007/s00262-007-0328-x

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