A current paradigm in immunology is that the strength of T cell responses is governed by antigen dose, localization, and costimulatory signals. This study investigates the influence of antigen kinetics on CD8 T cell responses in mice. A fixed cumulative antigen dose was administered by different schedules to produce distinct dose-kinetics. Antigenic stimulation increasing exponentially over days was a stronger stimulus for CD8 T cells and antiviral immunity than a single dose or multiple dosing with daily equal doses. The same was observed for dendritic cell vaccination, with regard to T cell and anti-tumor responses, and for T cells stimulated in vitro. In conclusion, stimulation kinetics per se was shown to be a separate parameter of immunogenicity. These findings warrant a revision of current immunization models and have implications for vaccine development and immunotherapy.antigen presentation ͉ antiviral immunity ͉ CD8 T cell responses ͉ tumor vaccine

Previous studies have shown that singlestranded RNA (ssRNA) mixed with protamine forms particles and activates immune cells through Toll-like receptors (TLRs). We have found that the size of protamine-RNA particles generated depends on the electrolyte content when mixing the 2 components. Moreover, we have evidenced that (1) nanometric particles induce production of interferon-␣, whereas (2) micrometric particles mainly induce production of tumor necrosis factor-␣ (TNF-␣) in human immune cells. We found that the mechanisms underlying these observations are (1) nanoparticles but not microparticles are selectively phagocytosed by plasmacytoid dendritic cells (pDCs), which produce interferon-␣ and (2) monocytes that produce TNF-␣ have a higher activation threshold than that of pDCs. Thus, at the same time as sensing pathogen-associated molecular patterns such as ssRNA, the immune system distinguishes the size of the associated structure in such a way as to trigger the adapted antivirus (

Particle-mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen-specific cytotoxic T-cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY-ESO-1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T-cells among CD4-positive cells. The higher relative sensitivity of regulatory T-cells compared to other CD4-positive T-cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4-compartment in healthy people and cancer patients. Thus, by affecting regulatory T-cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T-cell response.Spontaneous and treatment-induced antitumor T-cell responses can help in controlling cancer development.

In this study, we have started to dissect the molecular basis of CD8 dependence of a high and low avidity CTL clone specific for the same peptide epitope. Using anti-CD8a and anti-CD8b antibodies, we found that cytotoxicity and IFN-c production by high but not by low avidity CTL was strongly CD8 dependent. We isolated the TCR genes of both types of CTL clones and used retroviral gene transfer to analyse the function of these TCR in primary T cells of wild-type and CD8b-deficient mice. Both TCR triggered antigen-specific killing in wild-type T cells, and blocking experiments showed that CD8 dependence/independence co-transferred with the TCR into primary T cells, indicating that it was dictated by the TCR itself. Gene transfer experiments into CD8b-deficient T cells revealed that only the TCR derived from the CD8-independent CTL clone elicited antigen-specific cytotoxicity, while the CD8-dependent TCR was non-functional in the absence of the CD8b-chain. These data indicate a striking difference between CD8a/b heterodimers and CD8a/a homodimers as only the former were able to provide coreceptor function for the CD8-dependent TCR.

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The last decades have shown an increasing incidence of allergic illnesses such as rhinoconjunctivitis, with a prevalence of 20-30% in some industrialised parts of the world. The only treatment that may change the natural course of allergic disease is allergen-specific immunotherapy (SIT), which has been shown to prevent the development of asthma in rhinitic patients and anaphylaxis in insect venom allergic patients. However, the risk-benefit ratio for subcutaneous immunotherapy has changed little from when it was first developed in 1911. Novel developments of adjuvants, and allergens as well as methods of administration, now offer improvements in both the efficacy and safety of SIT. This review describes and discusses these new developments in the context of the many recent advances in our understanding of the mechanisms by which immunotherapy appears to act.

The CD8αβ heterodimer is integral to the selection of the class I-restricted lineage in the thymus; however, the contribution of the CD8β chain to coreceptor function is poorly understood. To understand whether the CD8β membrane proximal stalk region played a role in coreceptor function, we substituted it with the corresponding sequence from the CD8α polypeptide and expressed the hybrid molecule in transgenic mice in place of endogenous CD8β. Although the stalk-swapped CD8β was expressed on the cell surface as a disulfide-bonded heterodimer at equivalent levels of expression to an endogenous CD8β molecule, it failed to restore selection of CD8+ class I MHC-restricted T cells and it altered the response of peripheral T cells. Thus, the stalk region of the CD8β polypeptide has an essential role in ensuring functionality of the CD8αβ heterodimer and its replacement compromises the interaction of CD8 with peptide-MHC complexes.