TCR beta chain gene expression of individual T cell clones that share the same MHC class II restriction and similar fine specificity for the encephalitogenic NH2 terminus of the autoantigen myelin basic protein (MBP) has been examined. TCR V beta expression was examined by FACS analysis with mAbs specific for the V beta 8 subfamily of TCR beta chain genes. 14 of 18 (78%) NH2-terminal MBP-specific clones examined express a member of the TCR V beta 8 subfamily. Southern analysis was used to identify which member(s) of the TCR V beta 8 subfamily is expressed by these clones. Each of four clones examined uses V beta 8.2, though two different V beta 8.2-J beta 2 combinations were identified. Our findings indicate that there is restricted TCR V beta usage in the autoimmune T cell response to the dominant encephalitogenic NH2-terminal epitope of the MBP. The use of an mAb to the antigen-specific TCR in the prevention of T cell-mediated autoimmune disease has been investigated. Our results demonstrate that in vivo administration of a TCR V beta 8-specific mAb prevents induction of autoimmune encephalomyelitis.
The development of vaccines capable of inducing protective immunity against mycobacterial infection depends in part on the identification of antigenic determinants that activate T cells with antimycobacterial effector function. Various approaches designed to analyze the recognition of mycobacterial antigens by T cells are reviewed. In addition to the established approach of using serologically defined antigens, alternative methods independent of antibody preselection, such as polyacrylamide gel electrophoresis-fractionated immunoblots of mycobacteria, can be used to probe the specificity of the T cell repertoire. Furthermore, the application of recombinant DNA expression combined with that of synthetic pep tides whose sequences are predicted to constitute T cell determinants allow the localization of T cell epitopes within a protein. The use of these techniques in defining potentially “pathogenic and protective” T cell epitopes in mycobacteria is discussed.
Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian’s progressive interpretations of trees serve as a heuristic.
Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Abstract Neuron L11 in the abdominal ganglion of Aplysia californica is thought to be both cholinergic and peptidergic. In previous studies, we isolated a cDNA clone encoding the precursor for an L11 secreted protein(s) by differentially screening an abdominal ganglion cDNA library. We now report the isolation of genomic clones encoding the L11 cDNA sequences. Analysis of these clones reveals that the gene is present in a single copy per haploid genome. RNA blotting and cDNA cloning demonstrate that the L11 gene is expressed not only in the abdominal ganglion but in the head ganglia as well. To define the positions of cells expressing this gene and to follow their processes, we raised antibodies to synthetic peptides defined by the cDNA sequence. Histochemistry revealed about 100 neurons containing immunoreactive material. These cells arborize in the neuropil and are distributed throughout the central nervous system, representing about 0.5% of the Aplysia central neurons. In addition, cells in the abdominal ganglion send processes to the mantle floor at the base of the gill via the genital and branchial nerves. Our data suggest that this network of cells expresses the single L11 peptide gene.
The economics of vaccines has been a major limitation in the commercial research and development of new approaches. This coupled with the natural scientific desire to simplify and define the composition of effective vaccines argues that the future of vaccines lies in novel approaches that will discover effective and less expensive components. Peptides, whether they are chemically synthesized or produced in bacteria, are an attractive possibility. To substitute linear peptides for complex mixtures of proteins would be a major technical advance and would stimulate tremendous commercial interest. However, at the present time I view this approach still unlikely to be of major practical importance. I conclude this because of the complexity of immunological responses to microorganisms. Even though, in some instances, a cytotoxic T-cell response or even the majority of the antibody response to a pathogen can be defined by a short linear peptide, most people believe that multiple effector functions of the immune system should be stimulated in optimal vaccines. For a small cocktail of peptides to reproduce the diversity of responses elicited by a virus, parasite, or bacterium is unlikely. However, I fully realize that remarkable progress has occurred towards understanding the structural requirements necessary to stimulate cellular and humoral immune responses, and peptides have been integral in the development of this field. Also, the success of several research groups in developing effective antiviral vaccines using short linear peptides argues that I might be painting too dark of a picture. As someone who has used this strategy to explore peptide-MHC and peptide-antibody interactions, I am a strong scientific supporter of the approach. In this forum I am purposely cautious in my optimism. As the details of the complex molecular and cellular interactions that control the immune system are elucidated, both the number of strategies and the possible applications of modulating the immune response will increase as well. In addition to protective immunity to pathogens, cancer therapy could be revolutionized if tumor-specific cytotoxic T-cells could be generated routinely. Novel therapeutic approaches to allergy, autoimmunity, and transplantation can be envisioned if the T-lymphocytes responsible for these syndromes could be modulated without total immune suppression. Consequently, I am confident that the experiments described in this chapter will be central to developing exciting new therapeutic and prophylactic compounds, but I am not sure that they will resemble naturally occurring peptides. The one aspect I am confident of is that the capacity of the immune response to protect the organism will continually surprise us.
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