Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme.
Curr Opin Immunol. 2012 Jan 30;
Authors: Krüger E, Kloetzel PM
Abstract
The immunoproteasome is a specific proteasome isoform induced by interferons. Its proteolytic function has been almost exclusively connected with the adaptive immune response and improved MHC class I antigen presentation. However, IFN-signaling also exposes cells to oxidative stress with concomitant production of nascent-oxidant damaged poly-ubiquitylated proteins. Here we discuss how immunoproteasomes protect cells against accumulation of toxic protein-aggregates and how i-proteasomes dysfunction associates with different diseases. We propose that the immunoproteasome has a central function at the interface between the innate and adaptive immune response and that its predominant protective innate function determines its favorable role in the adaptive immune response.
PMID: 22296715 [PubMed - as supplied by publisher]
The stromal network of the thymus provides a unique environment that supports the development of mature CD4(+) and CD8(+) T cells expressing a very diverse repertoire of T cell receptors (TCR) with limited reactivity to self-antigens. Thymic cortical epithelial cells (cTECs) are specialized antigen-presenting cells (APCs) that promote the positive selection of developing thymocytes while medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) induce central tolerance to self-antigens. Recent studies showed that cTECs express a unique set of proteases involved in the generation of self-peptides presented by major-histocompatibility encoded molecules (pMHC) and consequently may express a unique set of pMHC complexes. Conversely, the stromal cells of the medulla developed several mechanisms to mirror as closely as possible the constellation of self-peptides derived from peripheral tissues. Here, we discuss how these different features allow for the development of a highly diverse but poorly self-reactive repertoire of functional T cells.
PMID: 22296716 [PubMed - as supplied by publisher]
Making memory at birth: understanding the differentiation of natural killer T cells.
Curr Opin Immunol. 2012 Feb 1;
Authors: Engel I, Kronenberg M
Abstract
Glycolipid reactive natural killer T cells with an invariant TCR α-chain (iNKT cells) are a conserved population of T lymphocytes with a distinct anatomical distribution and functional properties. The differentiation pathway of iNKT cells branches off from mainstream thymocyte differentiation at the double positive stage, and recent work has revealed how signaling events early in the iNKT cell pathway imprint a memory-like behavior on these cells. Additionally, unique molecular interactions governing iNKT cell development and tissue distribution have been uncovered recently, building up our knowledge of the complex network of interactions that form this population. Novel autologous antigens for these cells have been identified, although it has not yet been resolved if there is single endogenous antigen responsible for both positive selection and/or peripheral activation.
PMID: 22305304 [PubMed - as supplied by publisher]
The nucleotide-binding domain leucine-rich repeat proteins (NLRs) represent the major class of intracellular innate immune receptors in plants and animals. Understanding their functions is a major challenge in immunology. This review highlights recent efforts toward elucidating NLR functions in human and plants. We compare unconventional aspects of NLR proteins across the two kingdoms. We review recent advances describing P-loop independent activation, nuclear-cytoplasmic trafficking, oligomerization and multimerization requirements for signaling, and for expanded functions beyond pathogen recognition by several NLR proteins.
PMID: 22305607 [PubMed - as supplied by publisher]
β5t-containing thymoproteasome: specific expression in thymic cortical epithelial cells and role in positive selection of CD8+ T cells.
Curr Opin Immunol. 2012 Jan 27;
Authors: Takahama Y, Takada K, Murata S, Tanaka K
Abstract
Proteasomes are multisubunit proteolytic complexes that degrade cytoplasmic and nuclear proteins in eukaryotes. Proteasome-dependent proteolysis contributes to various cellular processes, including misfolded protein degradation, signal transduction, and antigen presentation. The thymoproteasome is a form of proteasome that contains the vertebrate-specific catalytic subunit β5t specifically expressed by cortical epithelial cells in the thymus. The thymoproteasome is essential for the positive selection of CD8+ T cells that carry an immunocompetent repertoire of antigen recognition specificity. Here we summarize the structure and expression of the thymoproteasome and discuss how it regulates the positive selection of CD8+ T cells.
PMID: 22285892 [PubMed - as supplied by publisher]
Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer.
Curr Opin Immunol. 2012 Jan 27;
Authors: Chan CJ, Andrews DM, Smyth MJ
Abstract
Management of an immune response is achieved through a delicate balance of pro-inflammatory and anti-inflammatory mechanisms. Controlling this response requires co-operation between a multitude of immune cells that are in turn controlled by specific receptor-ligand interactions and cytokine networks. In the context of cancer, a major mechanism by which the immune system restrains disease is through the action of cytotoxic lymphocytes that include natural killer (NK) cells and CD8 T cells. Both of these cell types express a panoply of receptors that are able to control their responses in order to heighten the specificity of their effector function. An emerging class of such receptors on cytotoxic lymphocytes are a group of immunoglobulin superfamily members that interact with ligands of the nectin and nectin-like (necl) family. These receptors include CD226, TIGIT, CRTAM and CD96. This review will outline the immunobiology of these receptors, the contexts where their function is important, their role in tumour immunosurveillance, and how they may be utilised for therapeutic applications in cancer.
PMID: 22285893 [PubMed - as supplied by publisher]
CD200R signaling in tumor tolerance and inflammation: A tricky balance.
Curr Opin Immunol. 2012 Jan 19;
Authors: Rygiel TP, Meyaard L
Abstract
The inhibitory CD200-CD200 receptor (CD200R) interaction is essential to prevent massive inflammatory responses and immune pathology during microbial infection. Since CD200 expression on human malignancies is associated with tumor progression, CD200 blocking antibodies are currently tested in clinical trials to boost anti-tumor responses. Here we discuss that CD200-mediated suppression of anti-tumor responses may not only be mediated by the tumor itself, but also by CD200 expressed on healthy tissue. However, in cancers that benefit from inflammation, the blockade of CD200 could result in enhanced tumor growth. We conclude that CD200 blockade forms a potential therapeutic option to strengthen anti-tumor responses which is not restricted to treatment of CD200 expressing tumors.
PMID: 22264927 [PubMed - as supplied by publisher]
Transcriptional drivers of the T-cell lineage program.
Curr Opin Immunol. 2012 Jan 19;
Authors: Rothenberg EV
Abstract
The T-cell development program is specifically triggered by Notch-Delta signaling, but most transcription factors needed to establish T-cell lineage identity also have crossover roles in other hematopoietic lineages. This factor sharing complicates full definition of the core gene regulatory circuits required for T-cell specification. But new advances illuminate the roles of three of the most T-cell specific transcription factors. Commitment to the T-cell lineage is now shown to depend on Bcl11b, while initiation of the T-cell differentiation program begins earlier with the induction of TCF-1 (Tcf7 gene product) and GATA-3. Several reports now reveal how TCF-1 and GATA-3 are mobilized in early T cells and the pathways for their T-lineage specific effects.
PMID: 22264928 [PubMed - as supplied by publisher]
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