Logic and modality

In this thesis I consider and argue against various versions of the view that logical truth and necessity are identical. I criticise purely modalist accounts of logical consequence, according to which consequence is just necessary truth-preservation, and I also criticise views on which necessity is identified with some prior understanding of logical truth (as semantic validity, or substitutional validity, or as syntactic derivability). In the process I develop various systems of modal semantics in detail and investigate the logic of logical truth under various alternative hypotheses

Applying plant genomics to crop improvement

A report of the European Science Foundation-Wellcome Trust Conference on Crop Genomics, Trait Analysis and Breeding, Hinxton, UK, 8-11 November 2006

Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire

AbstractMaking use of mice deficient for terminal deoxynucleotidyl transferase (TdT) expression and a random peptide library, we have examined the diversity and peptide specificity of the neonatal T cell repertoire specific for a single H-2Db-restricted peptide. Consistent with the predicted decrease in repertoire diversity, polyclonal CTL lines and individual clones from different TdT° mice are more similar to each other than those from different wild-type mice in terms of their finger-prints of cross-reactivity to the library and their TCR sequences. We have also found that several TdT° CTL clones cross-react with many more library peptides than wild-type CTL clones. In a few instances, the degree of peptide promiscuity correlates with TCR sequence characteristics such as N region addition and homology-directed recombination, but not CDR3 loop length. Based on epitope titrations for each clone, TCR affinity for antigen is consistently high; thus, this reduced specificity for peptide may coincide with an accentuated affinity for the α helices of the MHC. Peptide promiscuity in the neonate may allow the relatively small numbers of T cells in the periphery to protect against a broader range of pathogens

Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs

Naive CD8+ T cells differentiate into protective memory-like cells after IL-2–anti–IL-2 complex treatment in vivo

An optimal CD8+ T cell response requires signals from the T cell receptor (TCR), co-stimulatory molecules, and cytokines. In most cases, the relative contribution of these signals to CD8+ T cell proliferation, accumulation, effector function, and differentiation to memory is unknown. Recent work (Boyman, O., M. Kovar, M.P. Rubinstein, C.D. Surh, and J. Sprent. 2006. Science. 311:1924–1927; Kamimura, D., Y. Sawa, M. Sato, E. Agung, T. Hirano, and M. Murakami. 2006. J. Immunol. 177:306–314) has shown that anti–interleukin (IL) 2 monoclonal antibodies that are neutralizing in vitro enhance the potency of IL-2 in vivo. We investigated the role of IL-2 signals in driving CD8+ T cell proliferation in the absence of TCR stimulation by foreign antigen. IL-2 signals induced rapid activation of signal transducer and activator of transcription 5 in all CD8+ T cells, both naive and memory phenotype, and promoted the differentiation of naive CD8+ T cells into effector cells. IL-2–anti–IL-2 complexes induced proliferation of naive CD8+ T cells in an environment with limited access to self–major histocompatibility complex (MHC) and when competition for self-MHC ligands was severe. After transfer into wild-type animals, IL-2–activated CD8+ T cells attained and maintained a central memory phenotype and protected against lethal bacterial infection. IL-2–anti–IL-2 complex–driven memory-like CD8+ T cells had incomplete cellular fitness compared with antigen-driven memory cells regarding homeostatic turnover and cytokine production. These results suggest that intense IL-2 signals, with limited contribution from the TCR, program the differentiation of protective memory-like CD8+ cells but are insufficient to guarantee overall cellular fitness