The Journal of Immunology, 2003, 170: 3937-3938.
Copyright © 2003 by The American Association of Immunologists
IN THIS ISSUE
Kaylene J. Kenyon and
Dorothy L. Buchhagen
Treating experimental colitis
Cells of the intestinal mucosa must maintain a tightly controlled immune response to the massive antigenic load represented by enteric bacteria; a dysregulated mucosal immune response has been associated with Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease. Mottet et al. (p. 3939
) examined the ability of CD4+CD25+ T regulatory cells to reverse established colitis, using a mouse model of inflammatory bowel disease in which colitis is induced by transfer of CD4+CD45RBhigh T cells into immunodeficient mice. They showed that clinical improvement was noticeable within two weeks after transfer of CD4+CD25+ but not CD4+CD45RBlowCD25- T cells. Compared with nontreated controls, CD4+CD25+ T cell recipient mice exhibited reduced wasting, an increased survival rate, decreased leukocytic infiltrates to the lamina propria, and improved intestinal pathology. The authors also showed that CD4+CD25+ T cells home to the mesenteric lymph node and lamina propria, where they proliferate. CD4+CD25+ T cells in the mesenteric lymph node and the lamina propria were shown to be in contact with both APC (CD11c+ cells) and CD4+CD45RBhigh T cell progeny. This study therefore presents CD4+CD25+ T regulatory cells as a possible therapy in inflammatory bowel disease.
Communicating coactivators
Chemokines such as monocyte chemoattractant protein-1 (MCP-1) play a significant role in the recruitment and activation of leukocytes in a variety of human diseases. The transcription of MCP-1 is induced by a number of inflammatory mediators, one of the most potent being TNF-
. Boekhoudt et al. (p. 4139
) examined chromatin remodeling, histone acetylation, and involvement of coactivators at the two upstream regulatory regions of the MCP-1 gene that are required for TNF-induced expression. The authors confirmed that these two sites, the proximal promoter and a distal enhancer, bind the transcription factors Sp1 and the p65 subunit of NF-
B (RelA), respectively. Using Sp1-/- or NF-B p65-/- cells, the authors found that TNF-induced changes in chromatin structure in the proximal and distal regulatory regions were dependent, in part, on both NF-B and Sp1. They found that binding of NF-B p65 to the distal region results in histone acetylation of, and Sp1 binding to, the proximal region. Their finding that CREB binding protein and p300 can act as coactivators during the induction of MCP-1 by TNF leads the authors to propose that coactivators may provide communication links between the widely separated proximal and distal regulatory regions.
Chimp TCR genes
The chimpanzee is currently the only species available as a laboratory animal model that can be infected with hepatitis C virus. Chimpanzees and humans have highly homologous genomes and a high degree of conservation has been predicted for their TCR V
repertoires. A study by Meyer-Olson et al. (p. 4161
) presents the first thorough analysis of chimpanzee TCR V genes. The authors generated and analyzed 796 cDNA clones corresponding to TCR V regions. They found that 25 human TCR V families were represented among the 42 chimp TCR V sequences identified. The chimp TCR V genes were grouped in families in a similar way to those in humans. The authors also detected four functionally rearranged chimp genes that are pseudogenes in the human, and showed that one of these sequences was used in a functional chimp viral specific CTL clone. Analysis of the similarities and differences in TCR genes between chimp and human should facilitate studies not only of hepatitis C, but of other diseases for which the chimp may be used as an animal model.
A new mode of interaction
Staphylococcal enterotoxins are superantigens that cause food poisoning and shock by eliciting massive T cell cytokine production. Unlike other protein Ags, superantigens are recognized by T cells without first being processed into peptides for presentation by MHC molecules. Instead, intact superantigen protein binds to the outside surface of MHC class II/peptide complex and, for bacterial superantigens studied to date, to the V region of many TCRs. In contrast, Peterson et al. (p. 4148
) now demonstrate that the superantigen staphylococcal enterotoxin H (SEH) stimulates T cells via the V domain of the TCR. Using real time RT-PCR, they showed that SEH induced a TCR V10-specific expansion of activated T cells, but no expansion of TCR V cells. Flow cytometry studies confirmed that SEH stimulation does not alter the levels of the TCR V chains examined. The development of preventative treatments for superantigen-induced illnesses may be influenced by the finding that SEH acts as a V-specific superantigen.
Got herpes?
Herpes simplex virus (HSV) is a prevalent human pathogen, causing infection in both immunocompetent and immunocompromised individuals. In a study of T cell responses to HSV, Posavad et al. (p. 4380
) describe the presence of HSV-specific T cells in immunocompetent individuals who lack detectable serum Abs to either HSV-1 or HSV-2. The detection of HSV-specific T cells occurred in six subjects with no history of oral/labial or genital herpes but whose sexual partners were HSV-2 infected. In four of the six individuals, CD4+ and CD8+ T cell responses to HSV persisted for up to 4 years, whereas responses of two individuals were transient. HSV and HSV DNA were undetectable in daily samplings of oral and genital mucosal secretions over a period of up to 4 months in the five individuals who participated in this portion of the study. T cells specific for epitopes of HIV have been previously described in seronegative individuals, as have T cells specific for hepatitis C and EBV. Whether the T cell responses in the HSV seronegative individuals described here are due to undetected infection or the acquisition of immunity in the absence of infection bears significantly on the design of potential vaccines.
Homing-in on TCR ligands
Peptide-MHC tetramers are used increasingly to phenotype Ag-specific CD8+ T cells. However, they lack the sensitivity in humans to provide detailed information about the numbers of TCR-ligands on single cells or the tissue distribution of TCR-ligand-bearing cells. Cohen et al. (p. 4349
) developed an approach that addressed those shortcomings. The authors isolated several recombinant Abs from a nonimmunized human Fab phage library that recognized a HLA-A2 allele complexed with the Tax11–19 peptide of HTLV-1. Three of the isolates, termed TCR-like Abs, were studied in detail. The Abs reacted specifically with a soluble HLA-A2/Tax peptide complex in ELISAs, with the complex on the surface of RMA-S cells transfected with the HLA-A2 gene and loaded with the Tax peptide or transfected with the Tax gene, and with the complex on HTLV-1-infected RSCD4 cells. As few as 100 HLA-A2/Tax complexes per cell were visualized by staining homogeneous populations of cells or mixtures of cells containing as few as 1% Tax-transfected cells. In situ detection of HLA-A2/Tax on fixed cells was demonstrated by immunohistochemistry. This phage-based approach may be useful in isolating and engineering recombinant Abs to target specific cells in cancer, viral infections and autoimmune diseases and in understanding molecular interactions between TCR and MHC-peptide complexes.
Signals from IRAK
The proinflammatory cytokine IL-18 is implicated in the pathology of inflammatory conditions such as lung injury, arthritis and inflammatory bowel disease, as well as being essential for host defense against severe infections. IL-18 signals through the heterodimeric IL-18R complex, made up of the binding chain IL-18R, a member of the IL-1R family, and the associating IL-18R chain. The IL-18R complex recruits the IL-1R-associated kinase (IRAK) and TNF receptor-associated factor-6 (TRAF-6), which ultimately leads to activation of NF-B. Although IRAK-1 plays a role in IL-18 signaling, IRAK-1-deficient mice show only partial impairment of IL-18 induced responses. Suzuki et al. (p. 4031
) therefore used IRAK-4-deficient mice to examine whether IRAK-4 might also be involved in IL-18 signaling. They showed that IL-18-induced responses such as NK cell activity, Th1 IFN-
production, and Th1 cell proliferation are greatly diminished in these mice. In addition, activation of both NF-B and AP-1 are inhibited in Th1 cells from IRAK-4-deficient mice. IRAK-4 therefore appears to be critical in the signaling of IL-18 and may present a therapeutic target in diseases in which IL-18 is implicated.
Activin A in asthma
Asthma continues to be a serious health concern in many parts of the world. The interaction between airway inflammation and structural remodeling of the airway wall is important in determining therapeutic and preventative treatments for asthma. During the allergic response, mast cells infiltrate airway smooth muscle, and airway smooth muscle cells proliferate and take part in structural remodeling. Using cDNA microarray analysis and real time RT-PCR, Cho et al. (p. 4045
) studied gene induction in mast cells. They found that the gene for activin A, a member of the TGF superfamily, was strongly induced upon activation of both human and murine mast cells in vitro. Activated, but not unstimulated, mast cells from both species secreted activin A in vitro. Secretion of activin A was increased in the airways of OVA-sensitized mice following intranasal challenge but was greatly reduced in mast cell-deficient mice. Immunofluorescence studies of human lung biopsy specimens showed that mast cells from asthmatic patients stained for activin A, whereas those from normal control subjects did not. The authors also showed that smooth muscle cells proliferate in response to activin A, indicating that activin A may have a role in airway remodeling in asthmatic patients.
Summaries written by Kaylene J. Kenyon, Ph.D. and Dorothy L. Buchhagen, Ph.D.
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