The onset and regulation of a specific immune response results from communication between T cells and antigen-presenting cells (APCs), which form molecular interactions at the site of cell-cell contact--and this is known as the immunological synapse. Initially, the immunological synapse was viewed as a stereotypical adhesion and signalling device with a defined molecular structure and signalling processes. However, as we discuss here, T-cell-APC interactions comprise a diverse range of contact modes and distinct molecular arrangements. These diverse interaction modes might define a molecular code, in which the differences in timing, spacing and molecular composition of the signalling platform determine the outcome of T-cell-APC interactions.

Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 antibodies into tumor-bearing mice results in tumor eradication mediated by CD8 ؉ T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40 ؊ , and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancerhost interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent ''license to kill'' signal.M ost solid tumors express MHC class I molecules but lack costimulatory molecules essential for appropriate CTL activation (1, 2). Therefore, presentation of tumor-derived antigens by professional antigen-presenting cells (APCs) is most likely required for optimal tumor-specific T cell induction (3-6). Such activation of naïve T cells is called cross-priming and was first demonstrated by Bevan (7). As naïve T cells are thought to recirculate within the lymphoid system, cross-presentation provides the immune system with a means to detect and respond to antigens that are expressed only in the periphery.An important factor determining the outcome of immune responses is the level of antigen expressed in the periphery (8). In the case of relatively low levels of antigen, antigen is not presented at sufficient levels to activate naïve T cells. This situation is associated with ignorance of the antigen by the immune system. In the case of higher antigen-expression levels, antigen will be (cross-)presented in sufficient quantities to be detected by naïve T cells. In this case, antigen-recognition can either lead to tolerance or immunity (9, 10). The outcome of antigen recognition by naïve T cells, i.e., tolerance or immunity, is thought to be the consequence of the activation state of professional APCs that (cross-)present the antigen. This activation state is strongly influenced by inflammatory stimuli as well as the action of CD4 ϩ T helper (Th) cells.Studies on the requirement of CD4 ϩ Th cells in cross-priming of cytotoxic T lymphocytes (CTL) showed that both Th cells and CTLs must recognize antigens presented on the same APC (11,12). The interaction between Th cell and APC is sufficient to convert the APC to a state that allows priming of antigen-specific CTL (13, 14), which explains the observation that infusion of antigen-specific Th cells can rescue autoreactive CTL from deletion, resulting in CTL-mediated autoimmun...

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy.

The fate of naive CD8+ T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c+ APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8+ CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.

BackgroundPrevalence of type 2 diabetes (T2D) is increasing worldwide. T2D prevention by lifestyle intervention is effective. Pragmatic scalable interventions are needed, with evidence to efficiently target and monitor such interventions. We report pooled analyses of data from three European trial cohorts: to analyse T2D incidence, sustained weight loss and utility of risk predictors.MethodsWe analysed data on 749 adults with impaired glucose tolerance (278 men and 471 women, mean age 56 years, mean BMI 31 kgm−2) recruited between 1993 and 2003, and randomised to intensive lifestyle intervention (I) or lifestyle advice control (C). The intervention aimed to increase physical activity, modify diet, and promote weight loss≥5%. Using Cox-regression survival analysis, we assessed T2D incidence and the impact on T2D incidence of sustained weight loss, and of baseline cut-point values of FINDRISC score, fasting plasma glucose (FPG), and HbA1c.ResultsMean follow-up duration was 3.1 years. T2D was diagnosed in 139 participants (I = 45/379, C = 94/370). Cumulative T2D incidence was 57% lower in the intervention compared with the control group (HR 0.42 (95% CI 0.29 to 0.60) P<0.001). Participants with ≥5% weight loss at one year had 65% lower T2D incidence (HR 0.35 (95% CI 0.22 to 0.56) P<0.001); maintaining ≥5% weight loss for two and three years further reduced T2D incidence. Recommended cut-points to identify those at high risk for T2D would have identified different proportions of European Diabetes Prevention Study (EDIPS) participants with similar hazard-ratios for intervention effect.ConclusionsPooled analysis of EDIPS trial data reinforces evidence for T2D prevention by lifestyle intervention. Analysis showed the preventive effect of ≥5% weight loss, especially if maintained long term, which has utility for intervention monitoring. Analysis of proposed cut-points demonstrates difficulties in balancing risk and benefit, to efficiently target interventions and suggests evidence is needed to define clinical policy.Trial registrationsThe Finnish Diabetes Prevention study, Helsinki, Finland: ClinicalTrials.gov; NCT00518167 The SLIM diabetes prevention study, Maastricht, The Netherlands: Clinical Trials.gov; NCT00381186 The EDIPS-Newcastle diabetes prevention study, Newcastle upon Tyne, UK: International Standard Randomised Controlled Trial Number; ISRCTN15670600.