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Protein interactions with V(D)J recombination signal sequences (RSSs) were mapped in complexes containing RAG1 with (M1/2) or without (M1) RAG2. In both complexes, RAG interactions with the DNA backbone are biased toward one side of the helix; nonamer contacts resemble those of Hin with hixL. In the M1 complex, DNA contacts are centered on the nonamer. In the M1/2 complex, protein-RSS interactions...
Lymphotoxin β receptor (LTβR) -/- mice were created by gene targeting. LTβR -/- mice lacked Peyer's patches, colon-associated lymphoid tissues, and all lymph nodes. Mucosa patrolling α E β 7high integrin + T cells were virtually absent. Spleens lost marginal zones; T/B cell segregation and follicular dendritic cell networks...
Three mutant immunoglobulin heavy chain (IgH) insertion mice were generated in which a targeted nonfunctional IgH passenger transgene was either devoid of promoter (pΔ) or was placed under the transcriptional control of either its own RNA polymerase II-dependent IgH promoter (pII) or a RNA polymerase I-dependent promoter (pl). While the transgene mutation-frequency (0.85%) in memory B cells of pl...
Linker or adapter proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. We describe here the identification of a novel B cell linker protein, termed BLNK, that interfaces the B cell receptor-associated Syk tyrosine kinase with PLCγ, the Vav guanine nucleotide exchange factor, and the Grb2 and Nck adapter proteins. Tyrosine phosphorylation of BLNK by...
MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1...
We investigated lymphotoxin (LT) and TNF function in lymph node genesis and cellular organization by manipulating LTβ-R and TNF-R signaling. Lymph nodes developed in LTα -/- mice treated in utero with agonist anti-LTβ-R monoclonal antibody. Thus, LTβ-R signaling mediates lymph node genesis. Surprisingly, mucosal lymph nodes that can develop independently of LTαβ/LTβ-R interaction...
The human IL-4 receptor contains a sequence (the I4R motif) centered on Y497 that, when phosphorylated, interacts with phosphotyrosine-binding (PTB) domain proteins. Here, we describe a PTB domain protein, FRIP, that is phosphorylated in response to cytokine stimulation. FRIP is related to the rasGAP-associated protein p62 dok and is bound by the N-terminal SH2 domain of rasGAP....
Primary responses to the hapten phenyloxazolone and chronic responses to environmental antigens occuring in Peyer's patches were analyzed in two different mismatch repair-deficient backgrounds. Paradoxically, whereas primary responses were found normal in MSH2- and only slightly diminished in PMS2-deficient mice, mutations in Peyer's patch B cells from both k.o. animals were reduced three times, the...
Self-reactive B cells Tg for both a bcI-x L death inhibitory gene and an Ig receptor recognizing hen egg lysozyme (HEL-Ig) efficiently escaped developmental arrest and deletion in mice expressing membrane-bound self-antigen (mHEL). In response to the same antigen, Tg HEL-Ig B cells not expressing bcI-x L were deleted, while cells expressing bcI-2 were arrested at the immature B stage...
Likely creation of mismatches during somatic hypermutation has stimulated interest in the effect of mismatch repair deficiency on the process. Analysis of unselected mutations in the 3' flank of V H rearrangements in germinal center B cells revealed that MSH2 deficiency caused a 5-fold reduced mutation accumulation. This might reflect ectopic effects of the Msh2 disruption; indeed, the mice...
Fas-deficient (Fas lpr/lpr ) mice constitutively expressing BcI-2 in myeloid cells by the hMRP8 promoter often develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic Fas lpr/lpr hMRP8bcI-2 animals form clonogenic blast colonies in vitro and can transfer disease to...
Expression of a dominant negative mutant IFNγR1 in murine SCK and K1735 tumor cells rendered them relatively unresponsive to IFNγ in vitro and more tumorigenic and less responsive to IL-12 therapy in vivo. IL-12 induced histologic evidence of ischemic damage only in IFNγ-responsive tumors, and in vivo Matrigel vascularization assays revealed that while IFNγ-responsive and -unresponsive tumor cells...
The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity...
Previous studies have analyzed the diversity of T cell responses upon immunization. Little is known, however, about the individual variability of naive repertoires and its influence on immune responses. In the present study, T cells specific for a K d -restricted epitope derived from HLA-A2 were purified from individual immunized mice using tetramers of MHC-peptide. Their TCRβ chains were...
Distinct subsets of γδ T cells expressing different Vγ and Vδ chains arise in ordered waves during thymic development. In the murine Jγ1-Cγ1 cluster, the Vγ3 gene segment is utilized earliest in fetal thymic development, in progenitors of dendritic epidermal T cells (DECs). The Vγ2 gene segment predominates in the late fetal stages and beyond, in cells destined for the secondary lymphoid organs. Using...
To study the in vivo role of IL-4-expressing cells, we developed a strategy to tag these cells, by generating mice in which one IL-4 allele was replaced with a cDNA encoding the human CD2 (huCD2) cell-surface molecule. Expression of the huCD2 reporter was, like IL-4, restricted to the appropriately polarized T helper 2 cells. However, most of the cells expressed only the IL-4 or the targeted allele...
Using a sensitive molecular marker for positive selection, the appearance of a particular functional TCR α chain sequence in cells from mice bearing a transgenic β chain, we address several aspects of intrathymic T cell development. First, by examining specific TCR prior to and after maturation, we demonstrate how a restricted TCR repertoire is positively selected from a highly diverse immature TCR...
We recently identified a fetal thymic developmental stage (NK1.1 + /CD117 lo ) that characterizes committed T/NK progenitors. We now report the existence of phenotypically and functionally identical T/NK progenitors in mouse fetal blood and spleen but not in fetal liver. These precursors are indistinguishable from previously characterized fetal blood ''prothymocytes'' (CD90 ...
As the rate of Ig gene hypermutation approximates the level of nucleotide discrimination of DNA polymerases (10 -3 to 10 -4 ), a local inhibition of proofreading and mismatch repair during semiconservative replication could generate the mutations introduced by the process. To address this question, we have constructed transgenic mice that carry a hypermutation substrate containing...
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