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SummaryT cells have the capacity to respond to ligands as full, weak, partial or null agonists, or indeed as antagonists. In the present paper, it is reported that staphylococcal enterotoxin B (SEB) mutated in a T cell receptor (TCR) contact site (SEBΔ61Y) behaves as an altered ligand for a T cell clone (AC20) that expresses the Vβ17 TCR. The T cells were partially activated by SEBΔ61Y, as shown by TCR down-modulation and up-regulation of the IL-2 receptor. However, these cells did not secrete IL-2, IL-3, IL-4 or IFN-γ, nor did they proliferate. Analysis of intracellular protein tyrosine phosphorylation after cellular activation provided further evidence that SEBΔ61Y could transduce a signal via the Vβ17 TCR. The events following receptor ligation were clearly different when the T cells were stimulated with SEB or SEBΔ61Y, manifested as both quantitatively and qualitatively different patterns of phosphorylation of intracellular substrates. In contrast, only quantitative differences were apparent when a transfectant expressing the same α/β TCR was stimulated with the different superantigens. Together, these results provide the first demonstration that altered TCR ligands are not restricted to peptides substituted at secondary TCR contact residues. Rather, an altered superantigenic ligand mutated in the TCR binding site can behave as a partial agonist. [ABSTRACT FROM AUTHOR]

The development of technology to measure antigen presentation in the secondary lymphoid system has provided the opportunity of analysing components of the host antitumour immune response that have, until now, been unavailable for study. In particular, this technology has enabled us to evaluate threshold levels of tumour antigen required for cross-presentation in draining lymph nodes, the duration of this antigen presentation and processes that regulate tumour antigen presentation. Thus, we have been able to dissect out the relationship between antigen presentation and the resultant development of effector function in class I-restricted T cells, as well as the role of regulatory CD4 cells. We have also used this technology to evaluate the effects of antitumour therapy on local antigen cross-presentation. [ABSTRACT FROM AUTHOR]

Class II multimer formation is an important event in immune recognition. Not only is multimerization a prerequisite for T cell activation, but it is a signal to APC. In the present article, we propose that multimerization can result in the specific removal of ligand complexes from the cell surface of the APC, an event which may influence the overall pattern of T cell reactivity. [ABSTRACT FROM AUTHOR]

CD4+ T cells are activated upon recognition of peptide antigen in the context of MHC class II molecules, expressed by specialized APC. In this study, we show that CD4+ T cells cross-compete for antigenic complexes on the surface of APC, inhibiting activation of other potentially reactive T cells of the same and differing specificities. T cells with either a higher affinity receptor for antigen or which have undergone prior activation compete more efficiently than low affinity or resting T cells. This implies that T-cell avidity for the APC is primarily responsible for the competitive advantage. We also provide evidence that the mechanism for competition is steric hindrance of the surface of the APC, rather than T-cell-mediated sequestration or internalization of antigenic complexes. This is because removal of competing T cells restores the antigenic potential of the APC, and APC fixation does not abrogate competition. Demonstration that competition for access to APC can also occur in vivo suggests that this process may represent a physiologically important mechanism for influencing the quality and quantity of CD4+ T-cell responses. [ABSTRACT FROM AUTHOR]

Summary In a recent study, a superantigen mutated in the TCR binding site (staphylococcal enterotoxin B (SEB)Δ61Y) was described, which behaved as a partial agonist for a Vβ17-expressing T-cell clone. Evidence is now presented to demonstrate that there is distinct heterogeneity in the response of primary T cells to this protein. Some Vβ17 T cells responded to SEBΔ61Y by modulating surface receptor expression consistent with activation, and by proliferating. Other Vβ17 T cells did not proliferate, nor did they display a receptor expression phenotype consistent with activation. However, when repeatedly exposed to the altered superantigen, some of these non-responders entered cell cycle. This pattern of responses was not recapitulated by providing additional costimulation via CD28, although such treatment did induce some of the ‘unresponsive’ Vβ17 T cells to upregulate the IL-2 receptor, indicative of partial activation. It was also found that the heterogeneous pattern could be replicated using very low doses of native SEB. The data are discussed in the context of models of T-cell activation in which differences in TCR ligand affinity and dose determine qualitatively different response phenotypes. [ABSTRACT FROM AUTHOR]

Introduction Regulatory T cells (Treg) play an important role in suppressing anti- immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti-cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg. Methods Tumor bearing BALB/c FoxP3.dtr transgenic mice were subjected to different treatment protocols, with or without Treg depletion and tumor growth and survival monitored. Results DTX specifically depleted Treg in a transient, dose-dependent manner. Treg depletion correlated with delayed tumor growth, increased effector T cell (Teff) activation, and enhanced survival in a range of solid tumors. Tumor regression was dependent on Teffs as depletion of both CD4 and CD8 T cells completely abrogated any survival benefit. Severe morbidity following Treg depletion was only observed, when consecutive doses of DTX were given during peak CD8 T cell activation, demonstrating that Treg can be depleted on multiple occasions, but only when CD8 T cell activation has returned to base line levels. Finally, we show that even minimal Treg depletion is sufficient to significantly improve the efficacy of tumor-peptide vaccination. Conclusions BALB/c.FoxP3.dtr mice are an ideal model to investigate the full therapeutic potential of Treg depletion to boost anti-tumor immunity. DTX-mediated Treg depletion is transient, dose-dependent, and leads to strong anti-tumor immunity and complete tumor regression at high doses, while enhancing the efficacy of tumor-specific vaccination at low doses. Together this data highlight the importance of Treg manipulation as a useful strategy for enhancing current and future cancer immunotherapies. [ABSTRACT FROM AUTHOR]