The adaptor protein FADD/MORT1 is essential for apoptosis induced by 'death receptors', such as Fas (APO-1/CD95), mediating aggregation and autocatalytic activation of caspase-8. Perhaps surprisingly, FADD and caspase-8 are also critical for mitogen-induced proliferation of T lymphocytes. We generated novel monoclonal antibodies specific for mouse FADD and caspase-8 to investigate whether cellular responses, apoptosis or proliferation, might be explained by differences in post-translational modification and subcellular localisation of these proteins. During both apoptosis signalling and mitogenic activation, FADD and caspase-8 aggregated in multiprotein complexes and formed caps at the plasma membrane but they did not colocalise with lipid rafts. Interestingly, mitogenic stimulation, but not Fas ligation, induced a unique post-translational modification of FADD. These different modifications may determine whether FADD and caspase-8 induce cell death or proliferation.
The immune system is a tightly regulated network that is able to maintain a balance of immune homeostasis under normal physiological conditions. Normally, when challenged with foreign antigen, specific appropriate responses are initiated that are aimed at restoring homeostasis. However under particular circumstances, this balance is not maintained and immune responses either under or over react. Cancer is an example of a situation where the immune response can be inefficient or unresponsive, resulting in uncontrolled growth of the cancer cells. Conversely, when the immune response over-reacts, this can result in conditions such as autoimmunity or pathology following infection. Many drug therapies have been developed that aim to alleviate or prevent such immune disorders and restore immune homeostasis. This review highlights recent advances in immunotherapies, with an emphasis on specific examples in the treatment of cancer, autoimmune disease (multiple sclerosis) and viral infection (respiratory syncytial virus).
Individuals living in malaria-endemic areas show generally low T cell responses to malaria Ags. In this study, we show murine dendritic cell (DC) interaction with parasitized erythrocytes (pRBC) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall T cell responses in vitro and in vivo. Moreover, within the naive T cell population, pRBC-treated DC were selectively deficient in priming CD8+ but not CD4+ T cells. Indeed, DC that had taken up pRBC were shown for the first time to efficiently prime CD4+ T cell responses to a known protective merozoite Ag, MSP4/5. In contrast, impaired priming resulted in decreases in both proliferation and cytokine production by CD8+ T cells. Deficient priming was observed to both a model and a Plasmodium berghei-specific CD8+ T cell epitope. The mechanisms underlying the inability of parasite-treated DC to prime CD8+ T cells were explored. pRBC treatment of DC from wild-type C57BL/6, but not from IL-10 knockout animals, suppressed DC-mediated T cell priming across a Transwell, suggesting active IL-10-dependent suppression. CD8+ T cells were arrested at the G0 stage of the cell cycle after two cell divisions post-Ag stimulation. The proliferation arrest was partially reversible by the addition of IL-2 or IL-7 to responder cultures. These results suggest that in malaria-endemic areas, priming of CD8+ T cell responses may be more difficult to induce via vaccination than the priming of CD4+ T cells. Moreover, pathogens may selectively target the CD8+ T cell arm of protective immunity for immune evasion.
Regulation of immune responses is crucial in order to maintain immunological self-tolerance. This is maintained in the periphery by a number of cell types that have the capacity to control and regulate immune responses, thus preventing reactivity to self while monitoring appropriate, non-exuberant responses to non-self-antigens. The various mechanisms of regulation will be discussed in this review together with how this knowledge could be used to develop better drugs and treatments for various diseases.
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