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CD28 costimulatory signals are required for lymphokine production and T cell proliferation. CD28 signaling recruits the intracellular proteins PI 3-kinase, ITK, and GRB-2/SOS. PI 3-kinase and GRB-2/SOS bind the CD28 cytoplasmic pYMNM motif via SH2 domains. We generated CD28 pYMNM mutants and found that Y191 mutation (Y 191 CD28F) disrupted both PI 3-kinase and GRB-2 binding, while M 194...
The immunodominant epitope of myelin basic protein, Ac1–9, is encephalitogenic in H-2 u mice. We have previously demonstrated that this epitope displays low affinity for I-A u and have suggested that the avidity of T cell recognition in the thymus may be compromised, enabling autoreactive T cells to escape self-tolerance. We have addressed this hypothesis directly by constructing transgenic...
Mannose-binding protein (MBP), C1q, the recognition component of the classical complement pathway, and pulmonary surfactant protein A (SP-A) are members of a family of molecules containing a collagen-like sequence contiguous with a noncollagen-like sequence, and usually having the properties of a lectin. C1q and SP-A have been shown to enhance monocyte FcR- and CR1-mediated phagocytosis, suggesting...
We report a detailed analysis of TCR Vα and Vβ chain expression on immature versus mature thymocytes of normal, TCRβ-transgenic, and TCRa-hemizygous mice. Chain pairing between TCR Va and Vβ chains is random on immature thymocytes, but individual chain pairs are selected in mature thymocytes. This indicates that Vα-Vβ chain pairing preferences are determined during thymic selection, and not as a result...
The origin of autoreactive CD4 − CD8 − T cells is largely unknown. In TCR transgenic (Tg) mice expressing the cognate class I MHCantigen, CD4 − CD8 − T cells differed depending on characteristics of Tg-TCR/antigen interaction. Tg-TCRJCD3 lo CD4 − CD8 − T cells expressing the NK1.1 marker were observed only for a Tg-TCR whose stimulation by antigen...
In experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139–151, we have previously shown that the disease is mediated by Th1 cells, which recognize tryptophan 144 as the primary TCR contact point. Here we describe an altered peptide ligand (APL), generated by a single amino acid substitution (tryptophan to glutsmine) at position 144 (0144), which inhibits...
Human Vγ2Vδ2 + T cells recognize mycobacterial non-peptide antigens, such as isopentenyl pyrophosphate, and their synthetic analogs, such as monoethyl phosphate, through a TCR-dependent process. Here, we examine the presentation of these antigens. Vγ2Vδ2 + T cells recognized secreted prenyl pyrophosphate antigens in the absence of other accessory cells but, under such conditions, required...
The goal of this study was to examine the in vivo site of autoantibody production in normal and autoimmune-prone mice. B cells were identified in tissue sections with IgM- and IgG2a-specific riboprobes that readily distinguished resting cells from antibody-forming cells (AFC). In normal mice, the few identifiable IgG2a-secreting cells were found in the red pulp. By contrast, in Ipr mice exceedingly...
The nonpolymorphic human class II molecule HLA-DM (DM) has been found to play a key role in antigen presentation by MHC class II molecules. HLA-DM and its murine equivalent H2-M are located intracellularly and are absent from the cell surface. In transfected HeLa cells, H2-M was transported to an endosomal compartment in the absence of invariant chain. A tyrosine-based targeting motif in the cytoplasmic...
The cell-triggering properties of BCR, TCR and FcR depend on structurally related immunoreceptor tyrosine-based activation motifs (ITAMs). FcγR1113 have no ITAM and do not trigger cell activation. When coaggregated to BCR, they inhibit B cell activation. We show here that, when coaggregated to these receptors, FcγRIIB inhibit FcϵRI-, FcγRIIA-, and TCR-dependent cell activation. Inhibition also affected...
Recognition of class I MHC antigens involves interaction between TCRs of cytotoxic T lymphocytes (CTL) and the two a helices of MHC molecules. Using a combined panel of H-2K b mutants selected by either a CTL clone or MAbs, we have shown evidence that the TCRs of 59 K b -specific CTL clones shared a common binding pattern on the H-2K b molecule. Mutations of amino acid residues...
The T cell receptor (TCR) σ locus lies within the TCR α locus and is excised from the chromosome by Vα-Jα rearrangement. We show here that σ sequences persist in a large fraction of the DNA from mature CD4 + CD8 − αβ + mouse thymocytes. Virtually all σ loci in these cells are rearranged and present in extrachromosomal DNA. In immature αβ lineage thymocytes (CD3 −/lo ...
Two waves of immunoglobulin gene rearrangements, first of the heavy, then of the light chain gene loci form functional immunoglobulin genes during B cell development. In mouse bone marrow the differential surface expression of B220 (CD45R), c-kit, CD25, and surrogate light chain as well as the cell cycle status allows FACS separation of the cells in which these two waves of rearrangements occur. The...
The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two 137 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function...
The ability of a human cytomegalovirus-encoded homolog of MHC class I molecules to serve as a peptide receptor was investigated. Sequencing of peptide material eluted from the purified viral protein revealed a mixture of endogenous peptides with characteristics similar to those eluted from conventional class 1 molecules, that is, anchor residues, and a predominance of short peptides derived from cytoplasmic...
The multichain T cell antigen receptor (TCR) is composed of an antigen binding ( α β) domain and associated signal-transducing complexes, the CD3 (γ, σ, and ϵ) and the ζ chains. The ζ chain (TCRζ) plays a key role in signal transduction. We show here that TCR ligation induces association of tyrosine-phosphorylated TCRζ with the detergent-insoluble cell fraction. The microfilament poison, cytochalasin...
The exquisite sensitivity of thymocytes to steroid-induced apoptosis, the steroidogenic potential of thymic epithelial cells, and the ability of steroid synthesis inhibitors to enhance antigen-specific deletion of thymocytes in fetal thymic organ cultures suggest a role for glucocorticoids in thymocyte development. To address this further, transgenic mice that express anti-sense transcripts to the...
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