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Chemokines guide lymphocytes from blood to secondary lymphoid organs by triggering integrin-dependent firm adhesion under vascular flow and directed migration of T and B lymphocytes within lymphoid tissue. Here, we analyze the roles of DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, and phosphoinositide-3-kinase (PI3K) during lymphocyte recirculation...
The reported affinity differences between CD28 and CTLA-4 binding to B7-1 and B7-2 may serve to selectively regulate CD28 and CTLA-4 function by differentially recruiting and/or stabilizing these molecules at the immunological synapse. Here we show that ligand binding is important for the accumulation of both CD28 and CTLA-4 at the synapse. While CD28 is recruited to the synapse in the absence of...
Recently, static and dynamic imaging methods have produced the first glimpses of the interactions between antigen-specific T cells and peptide-MHC-bearing antigen-presenting cells in the lymph nodes. Using data from these experiments, we produced a numerically, spatially, and temporally scaled simulation of the first 50 hr of the primary T cell-dependent immune response. The simulation highlights...
Both osteopontin (OPN) and natural killer T (NKT) cells play a role in the development of immunological disorders. We examined a functional link between OPN and NKT cells. Concanavalin A (Con A)-induced hepatitis is a well-characterized murine model of T cell-mediated liver diseases. Here, we show that NKT cells secrete OPN, which augments NKT cell activation and triggers neutrophil infiltration and...
Id3 -/- mice were found to have autoantibodies, lymphocytic infiltrates in, and decreased secretion by exocrine glands. Similar symptoms are found in primary Sjogren's Syndrome. In this issue of Immunity, Li and colleagues suggest an important role for Id3 function in T cell development and Sjogren's Syndrome.
Regulatory T cells (Tregs) limit autoimmunity but also attenuate the magnitude of antipathogen and antitumor immunity. Understanding the mechanism of Treg function and therapeutic manipulation of Tregs in vivo requires identification of Treg-selective receptors. A comparative analysis of gene expression arrays from antigen-specific CD4 + T cells differentiating to either an effector/memory...
The NF-κB-inducing kinase (NIK) induces proteolytic processing of NF-κB2/p100 and, hence, the generation of NF-κB dimers such as p52:RelB but was suggested not to signal for the processing of IκB. Here, we show that although the induction of IκB degradation in lymphocytes by TNF is independent of NIK, its induction by CD70, CD40 ligand, and BLyS/BAFF, which all also induce NF-κB2/p100 processing,...
Cytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells. Mutations in genes important for this pathway are associated with several human diseases. CD4 + T regulatory (Treg) cells have emerged as important in the control of immunopathological processes. We have previously shown that human adaptive Treg cells preferentially...
Signaling by receptors in the TNF receptor (TNFR) superfamily mediate biological outcomes ranging from inflammation to apoptosis and other forms of programmed cell death. How receptor signaling mediates these divergent responses is just beginning to be understood. Here, we discuss how receptor submembrane localization and the formation of alternate signaling complexes can alter the fate of cells stimulated...
T cell priming by dendritic cells (DC) from gut-associated lymphoid tissues gives rise to effector cells with pronounced gut tropism. The mechanism for DC-dependent imprinting of gut specificity has remained unknown. New findings point to retinoic acid, which is uniquely produced by intestinal DC, but not by DC from other lymphoid organs (; this issue of Immunity).
TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar...
Alterations of TGF-β signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-β or a dominant-negative TGF-βRII, we demonstrate that TGF-β signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a...
For a preferential homing of T cells to the gut, expression of the integrin α4β7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of α4β7 and CCR9 on T cells upon activation and imprints them with the gut tropism...
Sjogren's syndrome is an autoimmune disease with clinical hallmarks of keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth). The genetic basis of this autoimmune disease is poorly understood. Id3 is an immediate early-response gene in growth regulation and is involved in TCR-mediated T cell selection during T cell development. Here, we show that Id3-deficient mice develop many disease...
We have studied the role of the T cell receptor (TCR) β chain transmembrane and cytoplasmic domains (βTM/Cyto) in T cell signaling. Upon antigen stimulation, T lymphocytes expressing a TCR with mutant and βTM and Cyto domains accumulate in large numbers and are specifically defective in undergoing activation-induced cell death (AICD). The mutant TCR poorly recruits the protein adaptor Carma-1 and...
High LDL and/or low HDL are risk factors for atherosclerosis and are also a common clinical feature in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Here, we show that changes in lipid profiles that reflect atherosclerotic disease led to activation of skin murine dendritic cells (DCs) locally, promoted dermal inflammation, and induced lymph node hypertrophy. Paradoxically, DC...
IL-17A was cloned more than 10 years ago and six IL-17 family members (IL-17A-F) have subsequently been described. IL-17A is largely produced by activated memory T lymphocytes but stimulates innate immunity and host defense. IL-17A and IL-17F both mobilize neutrophils partly through granulopoeisis and CXC chemokine induction, as well as increased survival locally. IL-17A and IL-17F production by T...
TCR affinity and ligand off-rate have both been found to influence the degree of T cell activation by peptide-MHC. A report in this issue of Immunity finds that ligand off-rate does not correlate with antigen-specific peripheral T cell expansion. Moreover, the data point to the surprising notion that there exist TCR affinity thresholds and, once attained, T cells with higher affinity receptors have...
Activation of the B cell antigen receptor triggers phosphorylation of cytoplasmic and transmembrane adaptor proteins such as SLP-65 and NTAL, respectively. Specific phosphoacceptor sites in SLP-65 serve as docking sites for Ca 2+ -mobilizing enzymes Btk and PLC-γ2. Phosphorylated NTAL recruits the Grb2 linker, but downstream signaling cascades are unclear. We now show that receptor-induced...
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