CD28 is the best-known costimulatory receptor, and most of its effects are mediated through NF-B activation (47)

CD28 is the best-known costimulatory receptor, and most of its effects are mediated through NF-B activation (47). immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes. is an ancient pathogen that continues to cause substantial human disease. The success of as a chronic and persistent pathogen depends to great extent Doxazosin on its ability to manipulate the host immune response in diverse and paradoxical ways. triggers potent proinflammatory and antigen-specific T cell responses while, at the same time, it displays a wide arrange of immune evasion strategies, such as inhibition of intracellular killing and antigen processing (8, 18, 21, 23, 37, 40). Understanding the complex mechanisms by which regulates the host immune response is essential to developing more effective drug treatments and tuberculosis (TB) vaccines. T cells are critical for an effective immune response against infection is traditionally considered an indirect result of to regulate T cell function (21). However, direct interactions between molecules and T cells may occur when vesicles containing mycobacterial components are released by infected macrophages (5-7). Different molecules have been implicated in direct regulation of T cell function. PIM binds 51 integrin on CD4+ T cells and triggers T cell adhesion to fibronectin (45) and lipoarabinomannan inserts into the T cell Rabbit polyclonal to XRN2.Degradation of mRNA is a critical aspect of gene expression that occurs via the exoribonuclease.Exoribonuclease 2 (XRN2) is the human homologue of the Saccharomyces cerevisiae RAT1, whichfunctions as a nuclear 5′ to 3′ exoribonuclease and is essential for mRNA turnover and cell viability.XRN2 also processes rRNAs and small nucleolar RNAs (snoRNAs) in the nucleus. XRN2 movesalong with RNA polymerase II and gains access to the nascent RNA transcript after theendonucleolytic cleavage at the poly(A) site or at a second cotranscriptional cleavage site (CoTC).CoTC is an autocatalytic RNA structure that undergoes rapid self-cleavage and acts as a precursorto termination by presenting a free RNA 5′ end to be recognized by XRN2. XRN2 then travels in a5′-3′ direction like a guided torpedo and facilitates the dissociation of the RNA polymeraseelongation complex membrane, resulting in the inhibition of type I cytokine production (32, 48). ESAT-6 may directly inhibit gamma interferon (IFN-) secretion and T cell proliferation by interfering with T cell receptor (TCR) signaling (54). By directly controlling T cell function, molecules may influence development of protective responses. Therefore, identification of mycobacterial molecules that can bind to non-TCRs on T lymphocytes and influence activation, adhesion, or migration may not only provide new insights into the pathogenesis of infection and disease but also open new avenues for TB treatment and/or prevention. Toll-like receptors (TLRs) are pattern recognition receptors that trigger rapid antimicrobial responses (1). They are prototypic receptors of the innate immune system and are mainly expressed on APCs (macrophages and dendritic cells) and NK cells. Recent studies demonstrate that TLRs are also expressed on T lymphocytes, including CD4+, CD8+, and Foxp3+ regulatory T cells. TLR2, TLR5, and TLR7-TLR8 (TLR7/8) can provide a second signal for activation of T cells upon TCR engagement (3, 10, 25, 27, 30, 33). expresses several TLR ligands, including the cell membrane-associated lipoproteins LpqH (Rv3763), LprG (Rv1411c), and LprA (Rv1270c); cell wall glycolipids (TLR2); and mycobacterial DNA containing CpG motifs (TLR9) (18, 19, 28, 37, Doxazosin 41). Mycobacterial TLR2 ligands have diverse effects on cells of the innate immune system, such as the induction of cytokine production, costimulatory molecule expression, and major histocompatibility complex class II (MHC-II) expression (18, 19, 21, 37, 40). Recently, mycobacterial TLR2 ligands, including lipoprotein LpqH, were identified in exosomes secreted by infection. Here we identified liproproteins LprG and LpqH as major components of the lysate with direct costimulatory effects for CD4+ T cells. These effects were independent of APCs and mediated by engagement of TLR2/1 on the T cells. The lipoproteins LpqH and LprG upregulated Th1 cytokine secretion and cellular Doxazosin proliferation in response to immobilized anti-CD3. Although both memory (CD45RO+) and naive (CD45RA+) CD4+ T cells expressed TLR2, only memory cells responded to TLR2 ligands when stimulated with anti-CD3 simultaneously. Consequently, lipoproteins serve as primary costimulators of memory T cells. Lipoproteins induced NF-B activation in resting CD4+ T cells in the absence of TCR coengagement. Thus, TLR2 engagement alone triggered intracellular signaling, but upregulation of cytokine production and proliferation required coengagement of TCR. Our data extend previous reports of TLR2 Doxazosin expression by human CD4+ T cells and suggest that TLR2/TLR1 may have a particularly important role in maintenance of memory Th1 responses in infection. In addition, these findings support the use of TLR2 agonists as adjuvants in.

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