CD8 T cells resolve intracellular pathogens by responding to pathogen-derived peptides that are presented on the cell surface by MHC class I molecules. Although most pathogens encode a large variety of antigenic peptides, protective CD8 T cell responses target usually only a few of these. To determine the mechanism by which the IFN-γ-inducible proteasome (immuno) subunits enhance the ability of specific pathogen-derived peptides to elicit CD8 T cell responses, we generated a recombinant Listeria monocytogenes strain (rLM-E1) that secretes a model Ag encompassing the immunoproteasome-dependent E1B192–200 and immunoproteasome-independent E1A234–243 epitope. Analyses of Ag presentation showed that infected gene-deficient professional APCs, lacking the immunosubunits LMP7/iβ5 and MECL-1/iβ2, processed and presented the rLM-E1-derived E1B192–200 epitope but with delayed kinetics. E1A epitope processing proceeded normally in these cells. Accordingly, infected gene-deficient mice failed to respond to the otherwise immunodominant E1B192–200 epitope but mounted normal CD8 T cell responses to E1A234–243 which was processed by the same professional APCs, from the same rLM-E1 Ag. The inability of gene-deficient mice to respond to E1B192–200 was not explained by insufficient quantities of antigenic peptide, as splenic APC of 36-h-infected gene-deficient mice that presented the two E1 epitopes at steady state levels elicited responses to both E1B192–200 and E1A234–243 when transferred into LMP7+MECL-1-deficient mice. Taken together, our findings indicate that not absolute epitope quantities but early Ag-processing kinetics determine the ability of pathogen-derived peptides to elicit CD8 T cell responses, which is of importance for rational T cell vaccine design.

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The clinical application of monoclonal antibodies (mAbs) revolutionised the field of cancer therapy as it enabled the successful treatment of previously untreatable types of cancer. Different mechanisms play a role in the anti-tumour effect of mAbs and both target engagement with the Fab arm as well as Fc-mediated effector functions contribute to the efficacy of treatment. Because Ig isotypes differ in their ability to bind to FcRs on immune cells as well as in their ability to activate complement, they differ in the immune responses they activate. Therefore, the choice of antibody isotype for therapeutic mAbs is dictated by its intended mechanism of action. Considering that clinical efficacy of many mAbs is currently achieved only in subsets of patients, optimal isotype selection and Fc optimisation during antibody development may represent an important step towards improved patient outcome. Here, we discuss the current knowledge of the therapeutic effector functions of different isotypes and Fc-engineering strategies to improve mAbs application.

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UVB exposure of the skin is associated with amelioration of inflammatory diseases, which has been shown to be mediated by activated Tregs. Since we have recently shown that Tregs, for optimal functioning, are dependent on signals induced by the EGF-like growth factor AREG, we tested whether UVB-mediated immunosuppression is dependent on AREG. We irradiated C57BL/6 wt and AREG-/- mice with UVB light and sensitized them with DNFB. Mice then were challenged and ear swelling was measured. Our results show that UVB light irradiation suppressed ear swelling in wt but not in AREG-/- mice. To determine at what point AREG expression would be essential, we transferred lymphocytes isolated from lymph nodes of irradiated and sensitized wt mice into naïve wt or AREG-/- mice, that then were sensitized with DNFB and challenged. In contrast to wt recipients, AREG-/- mice lacked suppression upon challenge. Similar results were found when lymphocytes, derived from UVB-irradiated CD4cre x EGF-Rflox/flox or wt mice, were transferred into wt mice. Mice that had received lymphocytes from irradiated and sensitized wt mice were fully able to suppress challenge induced ear swelling, while those that had received lymphocytes derived from UVB-irradiated CD4cre x EGF-Rflox/flox showed a significantly decreased ability to suppress swelling. Our data shows that AREG at the site of inflammation is essential for UVB irradiation-induced and Treg mediated immunosuppression.