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CD30 is a member of the tumor necrosis factor receptor superfamily, preferentially expressed by T cells producing type 2 helper (Th2) cytokines, whose ligand (CD30L) has been Identified on B cells, activated macrophages, and a subset of activated T cells. We show here that cross-linking CD30 with an agonistic CD30-specific monoclonal antibody, as well as with CD30L + CD8 + T cell clones...
We used a “hit and run” gene targeting strategy to generate mice expressing only the p31 isoform of the conserved invariant (li) chain associated with major histocompatibility complex (MHC) class II molecules. Spleen cells from these mice appear indistinguishable from wild type with respect to class II subunit assembly, transport, peptide acquisition, surface expression, and the ability to present...
Mutations in the Bruton's tyrosine kinase (Btk) gene have been linked to severe early B cell developmental blocks in human X-linked agammaglobulinemia (XLA), and to milder B cell activation deficiencies in murine X-linked immune deficiency (Xid). To elucidate unequivocally potential Btk functions in mice, we generated mutations in embryonic stem cells, which eliminated the ability to encode Btk pleckstrin...
Class II-mediated signals play potential roles in B cell activation and antigen presentation. The regions of the class II molecule participating in B cell signaling are incompletely defined. Our prior analysis of structural requirements of the cytoplasmic domain of A β revealed that only the eight membrane-proximal residues are required for signaling. Here, we report that the sequence and...
The ability of the B cell antigen receptors (BCRs) to enhance MHC class II-restricted antigen presentation was ascribed to mlg-associated Igα/Igβ heterodimers. The relative role of Igα and Igβ subunits in antigen presentation was investigated by fusing their cytoplasmic tails to the extracellular and transmembrane domains of Fc receptors. Igα and Igβ chimera mediate antigen internalization and increase...
Initiation of cell-mediated immune responses requires processing of intracellular pathogens into peptide fragments and presentation of these fragments to effector T cells. In the past few years, considerable progress has been made in understanding the molecular mechanisms underlying antigen processing and presentation. In particular, recent work has led to an understanding of the function of HLA-DM...
MHC class II molecules associate with invariant chain (li) during biosynthesis. li facilitates folding of class II molecules, interferes with their association with peptides, and is involved in their transport. The murine li gene encodes two chains, p31 and p41. The role of these isoforms has been studied in vitro only in inappropriate antigen-presenting cells. To circumvent this problem, we have...
We have established a model system for analyzing the induction of self-tolerance among mature peripheral T cells in Vβ5 TCR Tg mice. Both CD4 + Vβ5 + and CD8 + Vβ5 + cells undergo a superantigen-driven chronic deletion in the periphery of IE − mice. Prior to their disappearance, CD4 + transgene-expressing cells are activated and then rendered anergic...
Invariant chain (li)-negative mice exhibit defects in MHC class II assembly and transport that results in reduced levels of surface class II, altered antigen presentation, and inefficient positive selection of CD4 + T cells. Many CD4 + T cells that do mature in li-negative mice express a cell surface phenotype consistent with aberrant positive selection or peripheral activation. Reconstitution...
The transcription factor Nur77, an orphan member of the nuclear hormone receptor superfamily, is highly expressed during T cell receptor-signaled apoptosis, suggesting a possible role for Nur77 in negative selection. We examined this by generating two sets of transgenic mice. In one set of mice, a dominant-negative Nur77 mutant is constitutively expressed and the other in which wild-type Nur77 protein...
Mutations in the gene encoding the protein tyrosine kinase Btk are associated with the human B cell immunodeficiency X-linked agammaglobulinemia (XLA). In the mouse, a point mutation in the Btk pleckstrin homology domain segregates with a milder X-linked immunodeficiency (xid). To assessthe importance of Btk function in murine lymphopoiesis, we generated multiple embryonic stem cell clones bearing...
To investigate the role of the receptor-type tyrosine kinase, c-kit and its ligand, stem cell factor (SCF) in T cell development, we analyzed c-kit (W/W) and SCF (SI/SI) deficient mice. We also engrafted wild-type or SCF-deficient fetal thymi onto wild-type recipient mice and analyzed the rate of proliferation by in vivo bromodeoxyuridine labeling. The results show that the most immature thymocyte...
The early stages of lymphold cell formation were studied by testing the differentiative potential of phenotypically defined subsets of CD34 + bone marrow cells. A subpopulation of CD34 + Lin − CD45RA + cells expressing CD10 was isolated by flow cytometry. Such cells are CD38 + , HLA-DR + , do not express significant levels of Thy-1 and c-kit, lack erythroid,...
Type 1 interferons a and R are found to be potent inhibitors of IL-7-induced growth of early B lineage cells, while having no effect on cell growth induced by IL-2, IL-3, IL-4, or autogenous factors. The combination of IL-7 and interferons α/β induces bcl-2 down-regulation and cell death by apoptosis. These conclusions were derived initially from experiments employing exogenous cytokines, but functional...
Fetal thymic and adult epithelial Vγ3 + and Vγ4 + T cells express γδ antigen receptors (TCR) with invariant junctions lacking N nucleotides. Using transgenic recombination substrates, we show that di- or trinucleotide repeats, either in the coding region or in P elements, have strong effects on the site of recombination. In other mice bearing a terminal deoxynucleotidyl transferase...
Interleukin-2 receptor α chain (IL-2Rα) expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes. Young mice that lack IL-2Rα have phenotypically normal development of T and B cells. However, as adults, these mice develop massive enlargement of peripheral lymphoid organs associated with polyclonal T and B cell expansion, which,...
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