We found that mature nontransformed CD4+ and CD8+ T lymphocytes could be made susceptible to T cell receptor(TcR)-mediated apoptosis by pretreatment with interleukin-4 (IL-4) or interleukin-2 (IL-2). The degree of susceptibility to death could be correlated with the level of cell cycling as measured by thymidine incorporation, cell doubling times, or the number of cells incorporating bromodeoxyuridine during S phase. However, using pharmacologic cell cycle blocking agents, we found that progression through the cell cycle was not required for cell death. Rather, we found that cells must be in a certain phase of the cell cycle to be susceptible to TcR-mediated death. Cells blocked in G1 phase were resistant to T cell receptor-induced apoptosis, whereas cells blocked in S phase were susceptible. These observations suggest that an important feature of growth lymphokines is their ability to drive T cells into portions of the cell cycle where they are sensitive to antigen receptor-induced apoptosis. Furthermore, these results provide additional evidence that the T cell growth lymphokines IL-2 and IL-4 may participate in the down-regulation of T cell responses by apoptosis-a pathway we have termed "propriocidal regulation".
Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.
Elevated levels of serotonin (5-hydroxytryptamine, 5-HT) are observed in the serum of asthmatics. Herein, we demonstrate that 5-HT functions independently as an eosinophil chemoattractant that acts additively with eotaxin. 5-HT2A receptor antagonists (including MDL-100907 and cyproheptadine (CYP)) were found to inhibit 5-HT-induced, but not eotaxin-induced migration. Intravital microscopy studies revealed that eosinophils roll in response to 5-HT in venules under conditions of physiological shear stress, which could be blocked by pretreating eosinophils with CYP. OVA-induced pulmonary eosinophilia in wild-type mice was significantly inhibited using CYP alone and maximally in combination with a CCR3 receptor antagonist. Interestingly, OVA-induced pulmonary eosinophilia in eotaxin-knockout (Eot−/−) mice was inhibited by treatment with the 5-HT2A but not CCR3 receptor antagonist. These results suggest that 5-HT is a potent eosinophil-active chemoattractant that can function additively with eotaxin and a dual CCR3/5-HT2A receptor antagonist may be more effective in blocking allergen-induced eosinophil recruitment.
The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet -cells of the pancreas.
Prostaglandin D(2), the ligand for the G protein-coupled receptors DP1 and CRTH2, has been implicated in the pathogenesis of the allergic response in diseases such as asthma, rhinitis, and atopic dermatitis. This prostanoid also fulfills a number of physiological, anti-inflammatory roles through its receptor DP1. We investigated the role of PGD(2) and CRTH2 in allergic pulmonary inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated inflammation caused by either acute or subchronic sensitization using the cockroach egg antigen. Gene expression and ELISA analysis revealed that there was reduced proinflammatory cytokine mRNA or protein produced, as well as a wide array of genes associated with the Th2-type proinflammatory response. Importantly, the CRTH2 antagonist reduced antigen-specific IgE, IgG1, and IgG2a antibody levels as well as decreased mucus deposition and leukocyte infiltration in the large airways. Collectively, these findings suggest that the PGD(2)-CRTH2 activation axis has a pivotal role in mediating the inflammation and the underlying immune response in a T cell-driven model of allergic airway inflammation.
The roles of mutational and recombinational processes in the diversification of the exon encoding the antigen binding site in the murine major histocompatibility complex class II geneAb were assessed by phylogenetic analysis of allelic nucleotide sequences. A total of 46 alleles ofAb exon 2 from 12 Mus species or subspecies and 2 Ratus species were sequenced after amplification by the polymerase chain reaction. Reliable allelic genealogies could not be determined by phylogenetic analyses, due to extensive homoplasy in the data set. This homoplasy results from the shuffling of polymorphisms between alleles by recombinational processes, indicating that polymorphisms in the antigen binding site encoded by Ab are generated by a combination of two processes. First, the accumulation of point mutations has produced highiy divergent polymorphic sequence motifs in five regions ofAb exon 2, each encoding a portion of the binding site. Some of these motifs have persisted as polymorphisms in rodents since before the divergence of mouse and rat (>10 million years ago). The second process mediating Ab diversification involves the shuffling of these polymorphic sequence motifs into numerous allelic combinations by repeated intraexonic recombination. Site-specific hyperrecombinational mechanisms are not involved in this process within the exon. We postulate that these mechanisms continuously generate new Ab alleles with highiy divergent binding sites from which alleles with advantageous antigen-binding properties are selectively maintained by some form of balancing selection.
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