Immunology and Infectious Disease Commons^™

Preventing Thymus Involution In K5.Cyclin D1 Transgenic Mice Sustains The Naïve T Cell Compartment With Age, Michelle L. Bolner

Dissertations & Theses (Open Access)

The thymus maintains T cell receptor (TCR) repertoire diversity through perpetual release of self-MHC restricted naive T cells. However, thymus involution during the aging process reduces naïve T cell output, leading to defective immune responsiveness to newly encountered antigens. We have found that early thymus involution precipitates the age-associated shift favoring memory T cell dominancy in young control mice. Furthermore, we have shown that age-related thymus involution is prevented in mice expressing a keratin 5 promoter-driven Cyclin D1 (K5.D1) transgene in thymic epithelial cells (TECs). Thymopoiesis occurs normally in K5.D1 transgenic thymi and sustains T cell output to prevent the …

Determining The Mechanisms Generating Soluble Il-15 Complexes, Scott Anthony

Dissertations & Theses (Open Access)

A diverse assortment of infectious pathogens and TLR agonists enhance the expression of Interleukin (IL)-15. Additionally, inducing lymphopenia enhances anti-tumor responses in an IL-15-dependent manner. Paradoxically, despite the limited expression of IL-15 during homeostasis, the role of IL-15 during the steady state is well-known, while its roles during inflammation and infections remain largely undefined. IL-15 uses a unique method of production and presentation to support the development and homeostasis of NK and CD8 T cells. IL-15 is produced with its high affinity IL-15Rα and this IL-15Rα/IL-15 complex is shuttled to the cell surface where it is presented in-trans or cleaved …

Role Of Stat3 In Human Nk Cell Functions, Prasad V. Phatarpekar

Dissertations & Theses (Open Access)

Natural Killer (NK) cells are cytotoxic lymphocytes, which play a critical role in the immune response against malignant cells and microbial infections. NK cells are equipped with activating receptors, which upon detecting ligands expressed on stressed cells induce cytolytic activity of NK cells. Stimulation of NK cell proliferation and priming of NK cytolytic capability are accomplished by cytokines, which mediate their signals mainly through JAK-STAT signaling pathway. Previously, we found that K562 cells genetically modified to express membrane bound IL-21 (mbIL-21), which predominantly activates STAT3, induce robust expansion and activation of human NK cells. Further investigations revealed role of STAT3 …

Plasmacytoid Dendritic Cell-Mediated Humoral Autoimmunity, Stephanie M. Dorta-Estremera Ph.D.

Dissertations & Theses (Open Access)

Humoral autoimmunity is characterized by the breakdown of B cell immune tolerance to self-antigens and consequent production of pathogenic autoantibodies. Plasmacytoid dendritic cells (pDCs), a potent type I interferon (IFN-I) producer, have been linked to the pathogenesis of systemic lupus erythematosus (SLE), a prototypic systemic humoral autoimmune disease. However, the cellular events that stimulate the development of humoral autoimmunity as a result of pDC activation have not been characterized. Moreover, the B cell subset(s) responsible for the generation of autoantibodies remains to be clearly identified.

The immunization of DNA-containing amyloids into non-autoimmune mice triggers the activation of pDCs and induction …

Defining The Molecular Networks Necessary For Thymus Fate And Organogenesis, Kaitlin A. Reeh

Dissertations & Theses (Open Access)

The thymus and parathyroid (PT) glands originate from endodermal progenitors in the bilateral third pharyngeal pouches (3^rd pps). By E11.5 during mouse development, cells committed to the thymus lineage express Foxn1 whereas PT-fated cells express Gcm2. While these transcription factors are required for organ-specific differentiation, the exact molecular mechanisms that specify endodermal progenitors to either the thymus or parathyroid lineage are not well defined. Tbx1 is initially expressed throughout the 3^rd pp endoderm, as it is required for segmentation of the pharyngeal apparatus, but is downregulated in the thymus-fated domain by E10.5. Despite the widely held notion …

Regulation Of Autoimmune Germinal Center Reaction By Tfh Cells And Application Of Tfr-Like Cells For The Treatment Of Autoimmune B Cell Responses, Young Uk Kim

Dissertations & Theses (Open Access)

Excessive follicular helper T (Tfh) cell responses to self-antigens are associated with antibody-mediated autoimmune diseases in humans including systemic lupus erythematosus (SLE). Numeral and functional aberrations of T regulatory T (Treg) cells are common in patients with autoimmune diseases. Although different types of immunosuppressive agents have been used clinically to treat antibody-mediated autoimmune diseases, they generally have side effects due to the lack of target-specificity. To minimalize the adverse effects, there is a need to develop target-specific therapeutics which specifically control auto-reactive B cell responses and auto-reactive Tfh cell responses. Recent studies unveiled that Foxp3⁺ Treg cells expressing CXCR5 …

Enhancement Of Hiv Persistence By Adipose Tissue, Jacob Couturier

Dissertations & Theses (Open Access)

A major challenge for HIV eradication is the persistence of cellular and anatomic viral reservoirs. The primary cellular reservoirs for HIV, memory CD4 T cells and macrophages, traffic into various tissues where most viral replication occurs, or in the case of virally-suppressed antiretroviral-treated patients, the virus becomes dormant and protected from drugs and immune responses. The major tissue reservoirs for HIV include lymphoid tissues such as lymph nodes, bone marrow, and gastrointestinal lymphoid tissues, but adipose tissues could potentially harbor HIV as well. Adipose tissues are ubiquitous connective tissues and major sites of infiltration and immune activity by T cells …

Src Homology 2 Domain-Containing 5’-Inositol Phosphatase-2 (Ship2) Is An Effector Of Lymphatic Dysfunction, Germaine D. Agollah

Dissertations & Theses (Open Access)

The lymphatic system is essential for the transport of excess fluid, protein, and foreign materials from interstitial tissues to lymph nodes; for immune surveillance, and to maintain fluid homeostasis. Dysregulated lymphatics can be attributed to pathological conditions including tumor metastasis, inflammation, chronic wounds, obesity, blood vascular disorders, and lymphedema. Of these, lymphedema is the most extreme of lymphatic disorders and is represented by a spectrum of symptoms ranging from mild, subtle presentation to severe, disfiguring, overt presentation. Lymphedema is more manageable in the early stages of disease but severely reduces quality of life with progression. Due to lack of molecular …

Characterization Of The Roles Of Carma3 And Bcl10 In Virus-Triggered Rig-I/Mavs Signaling Pathway, Zhicheng Zhou Mr

Dissertations & Theses (Open Access)

After RNA virus infection, the innate immunity utilizes RIG-I family of receptors in the cytoplasm to initiate the production of type-I IFNs and proinflammatory cytokines by mitochondrial protein MAVS, which forms a prion-like structure to recruit TBK1and IKK complex to activate IRF3 and NF-κB, respectively. Herein, we revealed the important roles of CARMA3 and BCL10 in RIG-I/MAVS signaling pathway for the first time. CARMA3 or BCL10 deficient cells exhibited partially defective NF-κB activation but hyperactivation of TBK1-IRF3 signaling pathway upon ssRNA virus infection. It led to less production of IL6 but more production of type I IFNs and resulted in …

The Effect Of Activation Induced Cytidine Deaminase Phosphorylation And Herpes Virus Uracil Dna Glycosylase On Antibody Diversification, Marc Macaluso

Dissertations & Theses (Open Access)

Activation-induced cytidine deaminase (AID) is a mutagenic enzyme that is expressed in mammalian B-cells and initiates the antibody diversification processes of somatic hypermuntation (SHM) and isotype class switch recombination (CSR). AID is targeted to the immunoglobulin gene locus where it deaminates cytosines to generate uracil residues in DNA. This generates guanine-uracil (U:G) mismatch lesion which are recognized by uracil DNA glycosylase (UNG), a DNA repair enzyme that removes uracil from DNA and triggers downstream repair of the lesion. While UNG is a ubiquitously expressed DNA repair enzyme, its recognition and removal of AID introduced uracils is essential in both SHM …

Selection Methods For Genetically-Modified T Cells: In Support Of Translational Therapy, David Rushworth

Dissertations & Theses (Open Access)

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity …