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The T cell repertoire is shaped by positive and negative selection of thymocytes that express low levels of T cell receptor (TCR) and both CD4 and CD8. TCR-mediated signals that determine these selection processes are only partly understood. Vav, a GDP-GTP exchange factor for Rho-family proteins, is tyrosine phosphorylated following TCR stimulation, suggesting that it may transduce TCR signals. We...
The immunoglobulin α (Igα)/Igβ heterodimer was detected on the surface of μ-negative proB cell lines in association with calnexin. The cross-linking of Igβ on proB cells freshly isolated from bone marrow of recombination activating gene (RAG)-2–deficient mice induced a rapid and transient tyrosine-phosphorylation of Igα as well as an array of intracellular proteins including Syk, PI3-kinase, Vav,...
In these studies, IFNγ-inducing factor (IGIF), unlike IL-12, did not drive Th1 development in BALB/c or C57BL/6 mice, but like IL-1α, potentiated IL-12–driven Th1 development in BALB/c mice. IGIF and IL-12 synergized for IFNγ production from Th1 cells. Unlike IL-1α, IGIF had no effect on Th2 cells. IGIF signaled through IRAK, IL-1 receptor–associated kinase, to induce nuclear translocation of p65/p50...
The analysis of T cell receptor α (TCRα) chains in mice transgenic for a TCRβ chain has allowed us to demonstrate a central role for self-peptides in the positive intrathymic selection of major histocompatibility complex (MHC) class II–restricted T cells. Analysis of specific Vα–Jα joins in mature CD4+ TCRhigh thymocytes and in peripheral CD4+ T cells revealed a limitation in amino-acid sequences...
The transcription factor Ikaros is a major determinant of lymphocyte differentiation. Mice homozygous for an Ikaros dominat-negative (DN−/−) mutation lack all cells of lymphoid origin, including T, B, and natural killer (NK) cells. Mice homozygous for an Ikaros null allele lack B and NK cells but display specific defects in T lymphocytes. Nonetheless, both Ikaros mutant lines make an excess of monocytes...
Efficient T cell activation requires the engagement of a variety of ligand/receptor molecules in addition to T cell receptor (TCR)–major histocompatibility complex (MHC)/peptide interactions. The leukocyte function antigen 1 (LFA-1) and the CD28 glycoprotein have both been implicated in T cell activation. The present study dissects the roles of LFA-1 and CD28 in the activation of naive virus-specific...
The products of minor histocompatibility (H ) loci are serious barriers to tissue transplantation even among major histocompatibility complex (MHC) identical individuals, frequently causing chronic graft rejection and graft versus host disease. Over 50 minor H loci map to mouse autosomal chromosomes but none are known at the molecular level. By expression cloning, we identified the H13 locus, a classical...
The coreceptors CD4 and CD8 play a crucial role during thymocyte development and T cell effector function, and their expression is developmentally regulated. To determine the underlying molecular mechanisms of CD8 gene regulation we cloned the murine CD8 gene locus from genomic libraries and analyzed this region for deoxyribonuclease (DNase I) hypersensitive sites (HSS). Here we report, using transgenic...
We have used gene targeted mutational approaches to assess the role of the T cell receptor α (TCRα) enhancer (Eα) in the control of TCRα and TCRδ gene rearrangement and expression. We show that Eα functions in cis to promote Vα to Jα rearrangement across the entire Jα locus, a distance of greater than 70 kb. We also show that Eα is required for normal αβ T cell development; in this lineage, Eα is...
Positive selection of CD4+CD8+ T cells to the CD4+CD8− helper and CD4−CD8+ cytotoxic lineages is a multistep process that involves complex regulation of coreceptor gene expression. By analyzing expression of a reporter gene in transgenic mice, we have identified a DNA segment, located between the murine CD8β and CD8α genes, that has enhancer activity restricted to CD8 lineage cells. Remarkably, this...
For a brief period during fetal lymph node organogenesis in mice, lymph node postcapillary high endothelial venules surprisingly express the Peyer's patch addressin MAdCAM-1. This expression allows initial seeding of this incipient structure by two unusual lymphocyte populations selectively expressing the Peyer's patch homing receptor integrin α4β7: CD4+CD3− oligolineage progenitors and TCR γδ+ T...
Genetic predisposition to rheumatoid arthritis (RA) is linked to the MHC class II allele HLA-DR4. The charge of the amino acid at DRβ71 in the peptide-binding site appears to be critical in discriminating DR molecules linked to increased disease susceptibility. We have determined the 2.5 Å x-ray structure of the DR4 molecule with the strongest linkage to RA (DRB1*0401) complexed with a human collagen...
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