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Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive...
The oncogenic EBV protein LMP1 mimics a dysregulated CD40 receptor in vitro. To compare CD40 and LMP1-mediated events in vivo, transgenic mice were engineered to express mouse CD40 (mCD40tg) or a protein with extracellular mCD40 and cytoplasmic LMP1 (mCD40-LMP1tg). Transgenic and CD40 -/- mice were bred so that only the transgenic CD40 molecule is expressed in B cells, macrophages,...
Naturally arising CD25 + CD4 + regulatory T cells (T R ) play an important role in the prevention of autoimmunity. TCR specificity is thought to play a critical role in T R development and function, but the repertoire and specificity of T R TCRs remain largely unknown. We find by sequencing of TRAV14 (Vα2) TCRα chains associated with a transgenic TCRβ chain...
The last fifteen years have seen a reemergence of interest in cancer immunosurveillance and a broadening of this concept into one termed cancer immunoediting. The latter, supported by strong experimental data derived from murine tumor models and provocative correlative data obtained by studying human cancer, holds that the immune system not only protects the host against development of primary nonviral...
An initial exposure to lipopolysaccharide (LPS) induces a transient state of hyporesponsiveness to a subsequent challenge with LPS. The mechanism underlying this phenomenon, termed endotoxin tolerance, remains poorly understood despite a recent resurgence of interest in this area. We demonstrate herein that SHIP -/- bone marrow-derived macrophages (BMmφs) and mast cells (BMMCs) do...
The immune system detects viral infections and mutations in parenchymal cells when antigens from these cells are crosspresented on MHC class I molecules of professional antigen-presenting cells (APC). Exogenous antigens are crosspresented through TAP-dependent (cytosolic) or poorly understood TAP-independent (vacuolar) pathways. The TAP-independent pathway is blocked by the cysteine protease inhibitor,...
Highlights from a Fundacion Juan March Interdisciplinary Meeting. CD8 + T cells (T CD8+ ) play a critical role in immunity to viruses. A central feature of antiviral T CD8+ responses is immunodominance: out of thousands of potential target peptides, only a handful generate measurable responses. A recent Fundacion Juan March Meeting brought together...
Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following...
Research into the biology of endotoxin (aka lipopolysaccharide; LPS) began well over 100 years ago and has had many unexpected turns. The phenomenon of endotoxin tolerance was among these and has engendered immense curiosity over the years. Sly and colleagues (this issue of Immunity) have taken an important step toward understanding the phenomenon of endotoxin tolerance and have enhanced our comprehension...
A central feature of the immune system is the migratory behavior of its cellular components. Thus, fully understanding the generation and maintenance of immune responses must include consideration of how hematopoietic cells home to, interact within, and exit from secondary lymphoid organs as well as peripheral tissues. Recent advances in in situ imaging techniques now permit direct observation of...
MICA molecules interact with the NKG2D-activating receptor on human NK and CD8 T cells. We investigated the participation of the MICA/NKG2D pathway in the destruction of intestinal epithelium by intraepithelial T lymphocytes (IEL) in Celiac disease and its premalignant complication, refractory sprue. We show that MICA is strongly expressed at epithelial cell surface in patients with active disease...
TCR transgenic mice that express a peptide antigen in keratinocytes develop a lethal CD8 T cell-dependent autoimmune disease. We employed an adoptive transfer system to understand this disease and show that transfer of low numbers of naive CD8 T cells into peptide transgenic mice caused chronic skin disease. The antigen-presenting cell that initiated this response was the epidermal Langerhans cell...
Many microbial pathogens employ antigenic variation as a strategy to evade the immune system, posing a challenge in vaccine development. To understand the requirements for immunity against such pathogens, we studied Borrelia hermsii, a relapsing fever bacterium. We found that mice deficient in T, follicular B, marginal zone B, or B1a lymphocytes resolved B. hersmii bacteremia and became resistant...
A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling...
The molecular regulation of the recruitment of initial signaling complexes at the TNF-R1 is poorly defined. We demonstrate here that within minutes internalized TNF-R1 (TNF receptosomes) recruits TRADD, FADD, and caspase-8 to establish the ''death-inducing signaling complex'' (DISC). In addition, we identified the TNF-R1 internalization domain (TRID) required for receptor endocytosis and provide evidence...
The initial application of two-photon imaging to the study of lymphoid tissues has provided a dramatic glimpse into how cells of the immune system move and interact in their native environments. In this review we summarize what we have learned so far and point out areas for future investigation using this approach.
Infiltration of lymphocytes in the small intestinal epithelium is a hallmark of active celiac disease. In this issue of Immunity, two papers uncover mechanisms controlling the cytolytic potential of these cells and provide evidence that lymphocyte killing of enterocytes is an important part of the celiac disease pathogenesis.
Recent advances in photonics, particularly multi-photon microscopy (MPM) and new molecular and genetic tools are empowering immunologists to answer longstanding unresolved questions in living animals. Using intravital microscopy (IVM) investigators are dissecting the cellular and molecular underpinnings controlling immune cell motility and interactions in tissues. Recent IVM work showed that T cell...
Although found predominantly in the peritoneal and pleural cavities, B-1 cells are also present in other peripheral tissues such as spleen and lung. While similar in surface phenotypes, such as CD5, all B-1 cells are not equivalent in their response to stimuli. Here, we report that the src family kinase Lck is required to confer the BCR hyporesponsiveness typical of CD5 + B-1 cells and appears...
Adaptive immune responses are initiated by interactions of T cells with antigen-presenting cells, but the basic nature of these interactions during an immune response in vivo has been a matter of speculation. While some in vitro systems provide evidence for stable interactions, referred to as immunological synapses, compelling evidence supports T cell activation through serial transient interactions...
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