Browsing by Subject "Chemokine receptor"
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Item Bioinformatic analysis of chicken chemokines, chemokine receptors, and Toll-like receptor 21(Texas A&M University, 2006-10-30) Wang, JixinChemokines triggered by Toll-like receptors (TLRs) are small chemoattractant proteins, which mainly regulate leukocyte trafficking in inflammatory reactions via interaction with G protein-coupled receptors. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this study, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to identify systematically chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. The TLR family represents evolutionarily conserved components of the patternrecognizing receptors (PRRs) of the innate immune system that recognize specific pathogen-associated molecular patterns (PAMPs) through their ectodomains (ECDs). TLR's ECDs contain 19 to 25 tandem copies of leucine-rich repeat (LRR) motifs. TLRs play important roles in the activation of pro-inflammatory cytokines, chemokines and modulation of antigen-specific adaptive immune responses. To date, nine TLRs have been reported in chicken, along with a non-functional TLR8. Two non-mammalian TLRs, TLR21 and TLR22, have been identified in pufferfish and zebrafish. The objectives of this study were to determine if there is the existence of chicken genes homologous to fish-specific TLRs, and if possible ligands of these receptors exist. After searching the chicken genome sequence and EST database, a novel chicken TLR homologous to fish TLR21 was identified. Phylogenetic analysis indicated that the identified chicken TLR is the orthologue of TLR21 in fish. Bioinformatic analysis of potential PAMP binding sites within LRR insertions showed that CpG DNA is the putative ligand of this receptor.Item The role of CCR4 and CCR7 in the establishment of central tolerance(2016-08) Hu, Zicheng; Ehrlich, Lauren; Maynard, Jennifer A; Tucker, Haley O; Jiang, Ning; Wallingford, John BT cells mediate adaptive immune responses against foreign pathogens, such as viruses and bacteria, or malignant cells. T cells rely on T cell receptors to recognize foreign or tumor antigens presented on MHC-I or MHC-II complexes. Upon antigen recognition, T cells are activated and carry out effector functions to eliminate the antigen bearing cells. Aberrant recognition of self-antigen, however, will cause damage to healthy tissue, leading to autoimmune diseases. To establish tolerance towards self-antigens, developing T cells in the thymus (thymocytes) undergo stringent selection processes. During their final stages of maturation, thymocytes are exposed to a wide range of self-antigens presented by antigen presenting cells (APCs), such as dendritic cells and medullary thymic epithelium cells, in the medullary region of the thymus. Auto-reactive thymocytes that recognize self-antigens either undergo apoptosis or are diverted into the regulatory T cell lineage. Regulatory T cells (Treg) directly suppress effector functions of autoreactive T cells. Thus, both deletion and diversion into the Treg lineage are critical for averting autoimmunity. The cellular and molecular mechanisms governing thymocyte tolerance induction are incompletely understood. In this dissertation, I describe previously unreported roles for the chemokine receptors CCR4 and CCR7 in the establishment of tolerance in thymus. In order for thymocytes to encounter the full range of antigens against which they could be autoreactive, they must undergo efficient interactions with APCs in the medulla. However, the mechanisms promoting thymocyte medullary entry and interactions with APCs therein are not well understood. In chapter 2, I demonstrate that CCR4 is required for medullary entry of the earliest subset of thymocytes that enters the medulla and promotes their interactions with dendritic cells, one of the two major APC types in the thymic medulla. In keeping with the importance of these two activities for the induction of self-tolerance, in the absence of CCR4, autoreactive T cells are not efficiently eliminated and autoimmunity ensues. Regulatory T cells suppress immune responses initiated by auto-reactive T cells that escaped from thymus, and are therefore essential for maintaining self-tolerance. The regulation of regulatory T cell differentiation in the thymus is not fully understood. In chapter 3, I identify a novel role for CCR7 in controlling thymic regulatory T cell generation. Interestingly, CCR7 does not contribute to regulatory T cell induction due to its expression by thymocytes; instead, CCR7 expression on DCs modulates regulatory T cell generation by altering the composition of the thymic DC compartment. I found that CCR7 promotes survival of Sirpα- dendritic cells, one of the two major subsets of dendritic cells in the thymus. In the absence of CCR7, Sirpα- dendritic cells are preferentially lost, enabling an increase in the relative abundance of Sirpα+ dendritic cells, which more efficiently promote regulatory T cell generation. As a result, regulatory T cell generation is increased in CCR7-deficient mice, especially at the early neonatal stage, when regulatory T cell induction is particularly critical for the establishment of self-tolerance. The novel functions of CCR4 and CCR7 discovered by our studies provide new insights into the cellular and molecular mechanisms that govern T cell tolerance induction and will provide rationale for development of new therapies for autoimmune disorders.