The intracellular events leading to cytotoxic T-lymphocyte (CTL) activation and the molecular mechanism of target-cell lysis remain largely unknown. Differential hybridization analysis of a library constructed from a cloned CTL line was used to identify sequences specifically expressed in CTL. Two clones were selected for extensive analysis. No evidence for expression of their mRNAs was found in helper T-cell lines, thymocytes, lipopolysaccharide-activated B cells, interferon-treated natural killer cells, and a number of nonlymphoid cells. Blot-hybridization analysis of CTL mRNA revealed that one clone detected a single 900-nucleotide mRNA, whereas the other hybridized to two mRNAs of 900 and 1200 nucleotides, respectively. The maximum expression of these mRNAs precedes the peak of cytotoxicity in an in vitro allogeneic or mitogen-induced cytotoxic response by 24 hr; thus, they both fulfill the primary prerequisite for genes encoding proteins that are important in either CTL activation or in the lytic process itself.
Cyclosporin A (CsA) is known as a nontoxic inhibitor of the immune response that is primarily employed in humans to prevent the rejection of allografts. We report here on a novel activity for this drug as an immunomodulator. CsA can either inhibit or facilitate the induction of delayed-type hypersensitivity (DTH) depending on the class of immune response that would be induced in the absence of the drug. The drug inhibits the in vivo and in vitro induction of DTH when antigen is given under conditions that normally result in the induction of this response. The same concentration or dose of CsA inhibits the in vitro and in vivo induction of an antibody response and the antigen induces DTH instead. An explanation for these different effects of CsA on the induction of DTH is proposed. This novel activity of CsA in modulating the immune response from an antibody to a cell-mediated mode may have clinical applications.
This report, the first of two, arose from a one-week workshop directed at discussing concepts of immune regulation, and focuses on immunological tolerance. We first outline the major ideas we thought sufficiently plausible to provide a context for discussing more controversial issues around tolerance. We then report on our discussion of different experiments that appear paradoxical in terms of the different, contemporary models of CD4 T cell inactivation/activation, and how such observations might be resolved in terms of insights provided by these contemporary models. These discussions bear on the plausibility of the Pathogen-Associated Molecular Pattern (PAMP), Danger and Two Step, Two Signal Models for the activation of naïve CD4 T cells. Some of the observations considered appear paradoxical in terms of the PAMP and Danger Models, but not with the Two Step, Two Signal Model. For example, genetically immunodeficient mice have been given foreign, sterile ectopic grafts, and the immune system allowed to develop once these grafts were well-healed in, and so in the absence of PAMPs or danger. The grafts were rejected, unexpected on the PAMP or Danger Models. We also discussed considerations and observations bearing on the widely held idea that antigen must crosslink the membrane Ig receptors of a B cell to initiate the generation of signal 1, or the alternative possibility that monovalent binding by antigen can do so. We favored the latter possibility, and discussed a particular model, "the Elbow Model," for how this might be achieved.
A quantitative cellular radioimmunoassay (CRIA) for histocompatibility typing is described. Chicken red blood cells (RBC) were incubated in microtiter plates with specific anti-MHC (B) alloantisera and the alloantibody bound measured indirectly by a second binding step with(125)I-labeled rabbit anti-chicken IgG. The assay is objective, highly consistent, and three to four orders of magnitude more sensitive than conventional hemagglutination assays. The new CRIA was used to detect minor subpopulations of cells in artificial cell mixtures; as few as 1% of relevant cells were easily detected. Erythrocyte chimerism was induced following the injection of B(2)/B(2) chicken embryos with B(15)/B(21) embryonic stem cells. Five weeks after hatching, erythrocyte chimerism was precisely quantitated by comparing the reaction of RBC from the putative chimeras with artificial cell mixtures using specific anti-B(15)/B(21) alloantisera. The percent varied from 13-40% in 13 chimeric animals. The new CRIA was also used for the sensitive detection of tumor-specific antigens on a T-cell lymphoma. An unexpected finding was that anti-B(15) alloantibody bound almost as well to B(15)/B(21) heterozygous RBC as to B(15)/B(15) homozygous cells, suggesting that either the concentration or the steric arrangement of B(15) alloantigen at the erythrocyte surface may not conform to conventional expectations.
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