The BH3 domain of Bcl-x(S) is required for inhibition of the antiapoptotic function of Bcl-x(L).

bcl-x is a member of the bcl-2 family of genes. The major protein product, Bcl-x(L), is a 233-amino-acid protein which has antiapoptotic properties. In contrast, one of the alternatively spliced transcripts of the bcl-x gene codes for the protein Bcl-x(S), which lacks 63 amino acids present in Bcl-x(L) and has proapoptotic activity.

The majority of H2-M3 is retained intracellularly in a peptide-receptive state and traffics to the cell surface in the presence of N-formylated peptides.

We used a new monoclonal antibody (mAb 130) to analyze the intracellular trafficking and surface expression of H2-M3, the major histocompatibility complex class Ib molecule that presents N-formylated peptides to cytotoxic T cells. M3 surface expression is undetectable in most cell types due to the paucity of endogenous antigen. M3 is induced on the cell surface by addition of high-affinity N-formylated peptides from mitochondria and listeria.

Manipulation of outer root sheath cell survival perturbs the hair-growth cycle.

Transgenic mice that overexpress the anti-apoptotic gene bcl-xL under the control of the keratin 14 promoter have significantly shorter hair than non-transgenic littermates. The deficit in hair length correlated with a decrease in the duration of anagen, the growth phase of the hair cycle. A prolongation in telogen, the resting phase of the hair cycle, was also observed in adult animals.

Experimental lyme arthritis in the absence of interleukin-4 or gamma interferon.

Genetic resistance and susceptibility to experimental Lyme arthritis have been linked with the production of interleukin-4 (IL-4) or gamma interferon (IFN-gamma), respectively. To determine the absolute requirement for these cytokines in disease outcome, we compared arthritis development in wild-type, IL-4-deficient (IL-4 degrees ), and IFN-gamma-deficient (IFN-gamma degrees ) mice. While susceptible C3H mice developed swelling of ankle joints during the second week of infection, this swelling was exacerbated in C3H IFN-gamma degrees mice.

The central effectors of cell death in the immune system.

The immune system relies on cell death to maintain lymphoid homeostasis and avoid disease. Recent evidence has indicated that the caspase family of cysteine proteases is a central effector in apoptotic cell death and is absolutely responsible for many of the morphological features of apoptosis. Cell death, however, can occur through caspase-independent and caspase-dependent pathways.

Expression of CD1d2 on thymocytes is not sufficient for the development of NK T cells in CD1d1-deficient mice.

CD1 is an MHC class I-like molecule that has been conserved throughout mammalian evolution. Unlike MHC class I molecules, CD1 can present unique nonprotein antigens to T cells. The murine CD1 locus contains two highly homologous genes, CD1d1 and CD1d2.

Genetic control of experimental lyme arthritis in the absence of specific immunity.

Host genetics play an important role in determining resistance or susceptibility to experimental Lyme arthritis. While specific immunity appears to regulate disease resolution, innate immunity appears to regulate disease severity. Intradermal infection with Borrelia burgdorferi yields severe arthritis in C3H/He (C3H) mice but only minimal arthritis in BALB/c mice.

Linear differentiation of cytotoxic effectors into memory T lymphocytes.

A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of naïve T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice.

Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface receptor expressed on activated T cells that can inhibit T cell responses induced by activation of the TCR and CD28. Studies with phosphorylated peptides based on the CTLA-4 intracellular domain have suggested that tyrosine phosphorylation of CTLA-4 may regulate its interactions with cytoplasmic proteins that could determine its intracellular trafficking and/or signal transduction. However, the kinase(s) that phosphorylate CTLA-4 remain uncharacterized.

Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms.

A hydrophobic cleft formed by the BH1, BH2 and BH3 domains of Bcl-xL is responsible for interactions between Bcl-xL and BH3-containing death agonists. Mutants were constructed which did not bind to Bax but retained anti-apoptotic activity. Since Bcl-xL can form an ion channel in synthetic lipid membranes, the possibility that this property has a role in heterodimerization-independent cell survival was tested by replacing amino acids within the predicted channel-forming domain with the corresponding amino acids from Bax.

Bcl-xL and Bcl-2 expression in squamous cell carcinoma of the head and neck.

Background: Inhibition of apoptosis, or programmed cell death, may be critical both in the development of cancer and in determining response to therapy. The authors examined the expression of two related apoptotic inhibitors, Bcl-2 and Bcl-xL, in pretreatment biopsies from a series of 42 patients with squamous cell carcinoma of the head and neck. The observed pattern of apoptotic inhibitor expression was compared with that of the p53 gene product, another factor implicated in carcinogenesis and therapeutic responsiveness.

Tissue distribution, regulation and intracellular localization of murine CD1 molecules.

CD1 molecules are MHC-unlinked class Ib molecules consisting of classical (human CD 1a-c) and non-classical subsets (human CD1d and murine CD1). The characterization of non-classical subsets of CD1 is limited due to the lack of reagents. In this study, we have generated two new anti-mouse CD1 monoclonal antibodies, 3H3 and 5C6, by immunization of hamsters with purified CD1 protein.

Activation of natural killer cells in arthritis-susceptible but not arthritis-resistant mouse strains following Borrelia burgdorferi infection.

Infection of susceptible mouse strains with Borrelia burgdorferi, the agent of Lyme disease, results in the development of arthritis. Components of the innate immune system may be important mediators of this pathology. To investigate the potential role of NK cells in development of experimental Lyme arthritis, we examined their activation in vivo in both resistant and susceptible mouse strains.

Impaired negative selection in CD28-deficient mice.

T cell antigen receptors (TCR) expressed on developing T cells can react with self-peptides presented by proteins encoded by the major histocompatibility complex (MHC). Depending on the relative strength of these interactions, thymocytes are either negatively selected as potentially autoreactive and deleted or positively selected to become mature T cells. Developmental selection may also be regulated by signals in addition to those mediated through the TCR.

Helper T cell differentiation is controlled by the cell cycle.

Helper T (Th) cell differentiation is highly regulated by cytokines but initiated by mitogens. By examining gene expression in discrete generations of dividing cells, we have delineated the relationship between proliferation and differentiation. Initial expression of IL-2 is cell cycle-independent, whereas effector cytokine expression is cell cycle-dependent.

B-cell development and maturation.

Approximately 85% of all non-Hodgkin's lymphomas arise from cells of the B lineage. Sequential stages of B-cell development have been defined by molecular markers, and these markers can be used to reclassify lymphoid malignancies as representing maturational arrest and immortalization at specific points in B-cell ontogeny. Several of the factors controlling the ordered rearrangement and expression of the immunoglobulin (Ig) genes have been identified.

Bcl-2-family proteins: the role of the BH3 domain in apoptosis.

Bcl-2-related proteins have come to occupy a prominent position in the realm of programmed cell death. Members of this fast-growing family are highly related in one or more specific regions, commonly referred to as Bcl-2 homology (BH) domains. BH domains contribute at multiple levels to the function of these proteins in cell death and survival.

Identification of a lectin that induces cell death in developing chicken B cells.

The bursa of Fabricius is required for the development of a diverse B cell repertoire in chickens. Bursal B cells are dependent on survival signals within the bursa and their removal from the bursa results in death by apoptosis. To find molecules that regulate B cell survival, a panel of mAb and lectins was screened for the ability to either accelerate or prevent B cell death in culture.

A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas.

The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-xL transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-xL transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate.

Clearance of Borrelia burgdorferi may not be required for resistance to experimental lyme arthritis.

Infection of inbred mouse strains with Borrelia burgdorferi results in the development of experimental Lyme arthritis. The degree of arthritic pathology has been suggested to correlate with the level of spirochete burden within tissues. To investigate this further, we infected resistant DBA/2 (DBA) and susceptible C3H/HeJ (C3H) mice in the hind footpads and monitored arthritis development for 21 days.

Control of Leishmania major by a monoclonal alpha beta T cell repertoire.

Little is known regarding the diversity of the host T cell response that is required to maintain immunologic control of microbial pathogens. Leishmania major persist as obligate intracellular parasites within macrophages of the mammalian host. Immunity is dependent upon activation of MHC class II-restricted T cells to an effector state capable of restricting growth and dissemination of the organisms.

A critical, invariant chain-independent role for H2-M in antigen presentation.

Antigen presentation by MHC class II (class II) is facilitated by the accessory molecules, invariant chain (Ii) and H2-M. Ii associates with class II during biosynthesis and promotes transport of class II to Ag-loading compartments. One function of H2-M is the removal of Ii fragments from MHC class II.