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How cytotoxic T lymphocytes (CTLs) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. By using mice deficient in Serine Protease Inhibitor 6 (Spi6), we show that by inhibiting granzyme B (GrB), Spi6 protects CTLs from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) revealed...
Allelic exclusion ensures that individual B lymphocytes produce only one kind of antibody molecule. Previous studies have shown that allelic exclusion of the mouse Igκ locus occurs by the combination of monoallelic silencing and a low level of monoallelic activation for rearrangement combined with a negative feedback loop blocking additional functional rearrangements. Using yeast artificial chromosome-based...
Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID), which preferentially deaminates deoxycytidines at WRC (W = A/T, R = A/G) motifs in vitro. The mechanisms responsible for targeting AID and for organizing the queue of enzymes involved in vivo have been elusive. Here, we examined point mutant knockin Msh6 mice (Msh6 TD/TD...
We previously reported that the mice deficient for SPA-1, a Rap1 GTPase-activating protein, developed hematopoietic stem cell disorders. Here, we demonstrate that SPA-1 −/− mice show an age-dependent increase in B220 high B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1 −/− peritoneal B1 cells revealed the altered Vκ gene repertoire, including skewed...
The Drosophila host defense against gram-negative bacteria is mediated by the Imd pathway upon sensing of peptidoglycan by the peptidoglycan recognition protein (PGRP)-LC. Here we report a functional analysis of PGRP-LB, a catalytic member of the PGRP family. We show that PGRP-LB is a secreted protein regulated by the Imd pathway. Biochemical studies demonstrate that PGRP-LB is an amidase that specifically...
Antigen receptor gene assembly is governed by transcriptional promoters and enhancers that communicate over large distances and modulate chromatin accessibility to V(D)J recombinase. The precise role of these cis-acting elements in opening chromatin at recombinase targets and the mechanisms underlying their crosstalk remain unclear. We show that the TCRβ enhancer (Eβ) directs long-range chromatin...
Correlation between the promiscuity of the primary antibody response and conformational flexibility in a germline antibody was addressed by using germline antibody 36-65. Crystallographic analyses of the 36-65 Fab with three independent dodecapeptides provided mechanistic insights into the generation of antibody diversity. While four antigen-free Fab molecules provided a quantitative description of...
The control of IL-10 production and mechanisms that mediate synergy between IFN-γ and TLR ligands are not well understood. We report that IFN-γ augments induction of TNFα by TLR ligands, immune complexes, and zymosan by suppressing IL-10 production and thereby interrupting Stat3-mediated feedback inhibition. IFN-γ altered TLR2-induced signal transduction by increasing GSK3 activity and suppressing...
The mitochondrial antiviral signaling protein (MAVS) mediates the activation of NFκB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons...
Semaphorins play an essential role in axonal guidance, and emerging evidence points to diverse functions of several Semaphorin family members in the immune system. Semaphorin 7A (Sema7A) promotes axonal growth in the central nervous system. Here, we show that Sema7A also plays a critical role in negative regulation of T cell activation and function. T cells deficient in Sema7A exhibit enhanced homeostatic...
The serine kinase protein kinase D (PKD) has a cysteine-rich domain (CRD) that binds diacylglycerol (DAG) with high affinity. PKD is cytosolic in unstimulated T cells, but it rapidly polarizes to the immunological synapse in response to antigen/antigen presenting cells (APCs). PKD repositioning is determined by the accumulation of DAG at the immunological synapse and changes in DAG accessibility of...
Activated monocytes produce proinflammatory cytokines (monokines) such as interleukin (IL)-12, IL-15, and IL-18 for induction of interferon-γ (IFN-γ) by natural killer (NK) cells. NK cells provide the antiinflammatory cytokine transforming growth factor (TGF)-β, an autocrine/negative regulator of IFN-γ. The ability of one signaling pathway to prevail over the other is likely important in controlling...
Carbon monoxide (CO) suppresses proinflammatory responses in macrophages reacting to LPS. We hypothesize that CO acts by inducing a molecule(s) that suppresses the inflammatory response to subsequent stress. Exposure of macrophages to CO alone in vitro produced a brief burst of mitochondrial-derived ROS, which led to expression of PPARγ. PPARγ expression proved essential for mediating the anti-inflammatory...
The molecular basis of T cell anergy is not completely understood. We show that in antigen-primed anergic murine CD4 + T cells the linker for activation of T cells (LAT) is hypophosphorylated upon CD3/CD28 restimulation. Signaling events downstream of LAT (PLCγ1 phosphorylation and p85 [PI3-K] association) were impaired, whereas upstream events (CD3ζ and ZAP-70 phosphorylation) remained intact...
HIV-1-infected lymphocytes improperly respond to T cell antigen receptor (TCR) stimulation. To document this phenomenon, we studied the capacity of HIV-1-infected lymphocytes to form immunological synapses. We show here that HIV-1-infected T cells poorly conjugated with antigen-presenting cells, and when they formed conjugates, the synapses were abnormal. TCR and Lck accumulated in the recycling endosomal...
Intracellular proteins are degraded in the antigen processing pathway to generate peptide-loaded MHC I complexes (pMHC I) for immune surveillance. The characteristics of the final pMHC I are clear but those of their precursors and their potential binding partners remain poorly defined. By using a unique method to biochemically detect preprocessed ovalbumin-derived antigenic peptides, we find that...
The role of nitric oxide (NO) in T cells remains controversial, and the origin and localization of endogenous NO and whether it regulates lymphocyte activation are unclear. We show here that, within minutes of binding to antigen, T cells produce NO via endothelial nitric oxide synthase (eNOS). This process required increased intracellular Ca 2+ and phosphoinositide3-kinase activity. By using...
The maintenance of mature B cells hinges on signals emitted from the BAFF-R cell-surface receptor, but the nature of these signals is incompletely understood. Inhibition of canonical NF-κB transcription factor activity through ablation of the essential scaffold protein NEMO arrests B cell development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway by constitutively...
Calcium influx is crucial for T cell activation and differentiation. The detailed regulation of this process remains unclear. We report here that golli protein, an alternatively spliced product of the myelin basic protein gene, plays a critical role in regulating calcium influx in T cells. Golli-deficient T cells were hyperproliferative and showed enhanced calcium entry upon T cell receptor stimulation...
Here, we describe a previously unrecognized pathway for activation of antigen-specific adaptive immune responses that was independent of Toll-Interleukin 1 Receptor signaling and directed toward detection of antigens expressed by apoptotic cells. This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived...
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