[CITATION][C] Non‐MHC‐restricted cytotoxic cells: their roles in the control and treatment of leukaemias

MW Lowdell, L Lamb, C Hoyle… - British journal of …, 2001 - Wiley Online Library
MW Lowdell, L Lamb, C Hoyle, A Velardi, HG Prentice
British journal of haematology, 2001Wiley Online Library
The role of T lymphocytes in the MHC-restricted control and eradication of leukaemia after
allogeneic bone marrow transplantation is established, but there is increasing evidence that
the non-MHC-restricted cytotoxic lymphocytes have the capacity to lyse allogeneic or, in
some cases, autologous leukaemic blasts. Recently, the field of tumour immunotherapy has
been dominated by T cell-mediated approaches, probably as a result of the rapid and
significant advances in our understanding of the mechanisms involved in the generation of …
The role of T lymphocytes in the MHC-restricted control and eradication of leukaemia after allogeneic bone marrow transplantation is established, but there is increasing evidence that the non-MHC-restricted cytotoxic lymphocytes have the capacity to lyse allogeneic or, in some cases, autologous leukaemic blasts. Recently, the field of tumour immunotherapy has been dominated by T cell-mediated approaches, probably as a result of the rapid and significant advances in our understanding of the mechanisms involved in the generation of responses from naı» ve T cells. During the last 5 years, our knowledge of the activation and control mechanisms involved in non-MHC-restricted cell-mediated immunity has advanced enormously and we are now seeing a concomitant increase in the understanding of these cell types in tumour immunotherapy and in the immunotherapy of haematopoietic malignancies in particular. The termnon-MHC-restricted cytotoxic lymphocytes' encompasses natural killer (NK) cells, NK-T cells and gd T cells, all of which derive from a common lymphoid precursor cell but differentiate along separate pathways. NK-T and gd T cells express surface CD3 and the T-cell receptor (TCR); they are thus true T cells. NK-T cells express the a and b chains of the TCR while, as their name suggests, gd T cells express the g and d chain rearrangement. In contrast, NK cells lack both CD3 and TCR expression, but mostly (. 95%) express CD56 and/or CD16. Each cell type will be described in more detail including, when known, the mechanisms of antigen recognition, but in all cases this does not require MHC compatibility between effector and target cell, hence the termnon-MHC-restricted', although NK cells do recognize MHC molecules and this interaction is involved in their control of cytolysis. Expression of appropriate MHC molecules on target cells is inhibitory to NK cell-mediated lysis. Thus, NK cells are permanently ready to lyse potential target cells and can be triggered in a variety of ways. Cells showing downregulation of MHC molecules, such as some tumours and some virally infected cells, are innate targets owing to the lack of inhibition of NK-mediated lysis. Other cells with normal MHC expression can still be NK targets if they provide appropriate stimulatory signals, for example by ligation of the Fcg receptor (CD16), that are capable of overcoming the inhibition signals. While each of the cell types discussed here are distinct entities, they share several characteristics with respect to differentiation or cell surface antigen expression (Table I), but their relationships in the ontogeny of the cellular immune system have yet to be unravelled. All these cell types are involved in primary immune responses to tumours and intracellular pathogens, but lack the ability to generate amemory'subset to mediate secondary cellular responses to recall antigens.
The lack of requirement for MHC matching by these cells, indeed the potential benefit of mismatching in the case of natural killer cells, means that many clinical applications of these non-MHC-restricted cytotoxic cells are based upon allogeneic donor systems. However, the role of autologous natural killer cells in the cure of leukaemia is beginning to be unravelled and may lead to better defined trials of passive immunotherapy in the near future.
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