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An early history of T cell-mediated cytotoxicity


After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin–granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications.

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P.G. thanks Association pour la Recherche sur le Cancer for support and Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique and Aix Marseille University for institutional support to the Centre d’Immunologie de Marseille-Luminy (CIML). G.M.G. thanks the Wellcome Trust for research funding (grants 103930 and 100140). The authors thank all past and present members of their laboratories for their contributions to this research.

Reviewer information

Nature Reviews Immunology thanks J. Lieberman, J. Sprent and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors researched data for the article, discussed its content and wrote, reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Pierre Golstein or Gillian M. Griffiths.


51Cr release assay

An assay that evaluates the percentage of target cells that are lysed by cytotoxic T cells by measuring the proportion of radioactivity released from pre-labelled target cells.


A term that describes tissues or cells that are of the same species but are not genetically identical.

Antibody plaque formation

The ability of haemolytic antibody-forming lymphocytes to form plaques of lysed red blood cells in agar after being subjected to, for example, cytotoxic T cells.

Clonogenic assays

Assays used to determine the percentage of cells that are able to form colonies in vitro after being subjected to, for example, cytotoxic T cells.


A term that describes tissues or cells that genetically differ by only one chromosomal region.

Haemophagocytic lymphohistiocytosis

(HLH). A human autosomal recessive disorder that results from mutation of one of five genes, including the gene encoding perforin, and that leads to T cell hyperproliferation.


A graft from a donor of the same species as the recipient.

lpr mice

Mice bearing the lpr mutation of the Fas gene, which leads to a lymphoproliferative phenotype.


A term that describes tissues or cells that are genetically identical.


A term that describes tissues or cells that are of different species.

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Further reading

Fig. 1: Timeline of the history of research on CTLs.
Fig. 2: Chronological scheme of research on the mechanisms of CTL-mediated cytotoxicity.