Induction of pathogenic cytotoxic T lymphocyte tolerance by dendritic cells: a novel therapeutic target.
BACKGROUND
Dendritic cells (DCs) have an important role, both direct and indirect, in controlling the expansion and function of T cells. Of the different subsets of T cells, cytotoxic T lymphocytes (CTLs/CD8(+) T cells) have been implicated in the pathogenesis and development of many diseases, including various forms of autoimmunity and transplant rejection. It may therefore be of therapeutic benefit to control the function of CTL in order to modulate disease processes and to ameliorate disease symptoms. Currently, pharmacological approaches have been employed to either directly or indirectly modulate the function of T cells. However, these treatment strategies have many limitations. Many experimental data have suggested that it is possible to alter CTL activity through manipulation of DC.


METHODS
Novel strategies that condition DCs to influence disease outcome through manipulation of CTL activity, both directly and indirectly. This includes the modulation of co-stimulation, negative co-stimulation, as well as manipulation of the cytokine milieu during CTL generation. Furthermore, DCs may also impact CTL activity through effects on effector and regulatory cells, along with manipulation of bioenergetic regulation, apoptotic-cell mediated tolerance and through the generation of exosomes. The implications of related interventions in the clinical arena are in turn considered.


RESULTS
Insight into such indirect methods of controlling CTL activity allows for an understanding of how disease-specific T cells may be regulated, while also sparing other aspects of adaptive immunity for normal physiological function. Such an approach towards the treatment of disease represents an innovative therapeutic target in the clinical arena.


CONCLUSIONS
There are numerous innovative methods for using DCs to control CTL responses. Manipulation of this interaction is thus an attractive avenue for the treatment of disease, particularly those of immune dysregulation, such as seen in autoimmunity and transplantation. With the number of studies moving into clinical stages constantly increasing, further advances and successes in this area are inevitable.
Gill
Dipender
D
University of Oxford, John Radcliffe Hospital, Nuffield Department of Surgery, Headley Way, Oxford, OX3 9DU, UK.
Tan
Peng H
PH
D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D055354:Exosomes / Q000276:immunology / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D051381:Rats; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism