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Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter Jun 2016

Memory Cd8+ T Cell Function During Mycobacterium Tuberculosis Infection: A Dissertation, Stephen M. Carpenter

GSBS Dissertations and Theses

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the ...


The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon Apr 2012

The Subtype Specific And Cross-Reactive T Cell Responses To Influenza Viruses In Humans: A Dissertation, Jenny Aurielle B. Babon

GSBS Dissertations and Theses

Human influenza is a contagious respiratory disease resulting in substantial morbidity and mortality worldwide. With the recent cases of avian influenza infections in humans and the heightened concern for an influenza pandemic arising from these infections, it is essential to understand host responses that would confer protective immunity to influenza. The cell-mediated immune responses to influenza virus play an important role during influenza infection.

To analyze the specificity and diversity of memory T-cell responses, we performed a genome-wide screening of T cell epitopes to influenza A virus in healthy adult donors. We identified a total of 83 peptides, 54 of ...


Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra Feb 2012

Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra

GSBS Dissertations and Theses

T lymphocytes are distinguished by the expression of αβ TCR or γδ TCR on their cell surface. The kinetic differences in the effector functions classifies γδ T cells as innate-like lymphocytes and αβ T cells as adaptive lymphocytes. Although distinct, αβ and γδ T cell lineages produce a common array of cytokines to mount an effective immune response against a pathogen. The production of cytokine IL-17 is a shared characteristic between the γδ T (Tγδ17) cells and the CD4 T (Th17) cells. γδ T cells develop into Tγδ17 cells in the thymus whereas CD4 T cells differentiate into Th17 cells ...


Telomere Length Dynamics In Human T Cells: A Dissertation, Joel M. O'Bryan Oct 2011

Telomere Length Dynamics In Human T Cells: A Dissertation, Joel M. O'Bryan

GSBS Dissertations and Theses

Telomere length has been shown to be a critical determinant of T cell replicative capacity and in vivo persistence in humans. We evaluated telomere lengths in virus-specific T cells to understand how they may both shape and be changed by the maintenance of memory T cells during a subsequent virus re-infection or reactivation. We used longitudinal peripheral blood samples from healthy donors and samples from a long-term HCV clinical interferon therapy trial to test our hypotheses.

To assess T cell telomere lengths, I developed novel modifications to the flow cytometry fluorescence in situ hybridization (flowFISH) assay. These flowFISH modifications were ...


The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan Mar 2011

The Function Of Innate Γδ T Cell Subsets Is Molecularly Programmed In The Thymus In Three Stages: A Dissertation, Kavitha Narayan

GSBS Dissertations and Theses

The immune system generates discrete lineages of cells that are designed to respond optimally to environmental cues and infectious agents. Two distinct lineages of T cells, distinguished by expression of either an αβ or γδ T cell receptor (TCR), arise from a common progenitor in the thymus. The type of pathogen and the cytokine milieu directs effector differentiation of αβ T cells in the periphery through the induction of specific transcriptional networks. γδ T cell development is distinct from that of αβ T cells in its ordered rearrangement of TCR genes and the pairing of Vγ and Vδ chains to ...


T Cells Aid In Limiting Pathogen Burden And In Enhancing B1 And B2 Cell Antibody Responses To Membrane Glycolipid And The Surface Lipoprotein Decorin-Binding Protein A During Borrelia Burgdorferi Infection: A Dissertation, Robyn Lynn Marty-Roix Jun 2010

T Cells Aid In Limiting Pathogen Burden And In Enhancing B1 And B2 Cell Antibody Responses To Membrane Glycolipid And The Surface Lipoprotein Decorin-Binding Protein A During Borrelia Burgdorferi Infection: A Dissertation, Robyn Lynn Marty-Roix

GSBS Dissertations and Theses

Murine infection by the Lyme disease spirochete, B. burgdorferi, results in the generation of pathogen-specific antibody that can provide protection against Lyme disease, but the cells involved in this response are poorly characterized. T cells are not required for generating a protective antibody response to B. burgdorferi infection, but their exact role in providing protection against tissue colonization had not been previously determined. We found that TCRβxδ;-/- mice were susceptible to high pathogen loads and decreased antibody titers, but inhibition of CD40L-dependent interactions resulted in partial protection suggesting that a portion of the help provided by T cells was not ...


Multifaceted Regulation Of Peripheral T Cell Tolerance And Autoimmunity By Foxp3+ T Regulatory Cells: A Dissertation, Nitya Jain Jan 2009

Multifaceted Regulation Of Peripheral T Cell Tolerance And Autoimmunity By Foxp3+ T Regulatory Cells: A Dissertation, Nitya Jain

GSBS Dissertations and Theses

Adaptive immunity requires T cell responses to foreign pathogens to be counterbalanced with the need to limit collateral destruction of the host’s own tissues. Further, the presence of a substantial pool of lymphocytes capable of recognizing selfantigen in the periphery poses a threat to the maintenance of peripheral tolerance and prevention of autoimmunity. Regulatory T cells (Treg) that can suppress potentially self-reactive T cells are critical regulators of peripheral tolerance as well as initiation of immune responses. Treg cells employ several context-dependent mechanisms to establish regulation. In this thesis, we describe two distinct pathways of regulation used by Treg ...


Role Of Endoplasmic Reticulum Stress Response Signaling In T Cells: A Dissertation, Steven C. Pino Jul 2008

Role Of Endoplasmic Reticulum Stress Response Signaling In T Cells: A Dissertation, Steven C. Pino

GSBS Dissertations and Theses

T cells play a central role in cellular-mediated immunity and must become activated to participate as effector cells in the immune response. The activation process is highly intricate and involves stimulation of a number of downstream signaling pathways enabling T cells to proliferate and produce cytokines that are vital for proper effector function. This increase in protein production and protein folding activity adds to the normal physiological strain on cellular machinery. One cellular compartment that has generated a mechanism to mitigate the stress induced by increased protein production is the endoplasmic reticulum (ER).

In general, an increase in cellular production ...


Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar May 2006

Sox13, A Γδ T Cell-Specific Gene, Is A Wnt-Signaling Antagonist Regulating T Cell Development: A Dissertation, Heather J. Melichar

GSBS Dissertations and Theses

Mature αβ and γδ T cells arise from a common precursor population in the thymus. Much debate has focused on the mechanism of T cell lineage choice made by these multi-potential precursor cells. It is widely believed that the decision of these precursor cells to commit to the γδ or αβ T cell lineages is regulated primarily by a specific instructive signal relayed through the appropriate T cell receptor. Contrary to this model, we present evidence for a TCR-independent lineage commitment process. Comparison of global gene expression profiles from immature αβ and γδ lineage thymocytes identified Sox13, an HMG-box transcription ...


The Role Of ΓС Cytokines In T Cell Development, T Cell Homeostasis And Cd8+ T Cell Function: A Dissertation, Sara Gozalo May 2004

The Role Of ΓС Cytokines In T Cell Development, T Cell Homeostasis And Cd8+ T Cell Function: A Dissertation, Sara Gozalo

GSBS Dissertations and Theses

T lymphocytes are essential components of the immune system and as such are continually regulated by a variety of factors. Every step of their development, survival and function is tightly monitored to ensure their ability to recognize most foreign agents and mount adaptive immune responses during pathogenic infections, while remaining tolerant to self-antigens. Among the many factors that participate in the regulation of T cell development and function are the cytokines. Cytokines that signal through the common gamma (γс) chain and the Janus kinase 3 (Jak3) include IL-2, -4, -7, -9, -15, and -21 and have been implicated in ...


The Molecular Mechanisms Of T Cell Clonal Anergy: A Dissertation, John E. Harris Jun 2003

The Molecular Mechanisms Of T Cell Clonal Anergy: A Dissertation, John E. Harris

GSBS Dissertations and Theses

A side effect of generating an immune system for defense against invading pathogens is the potential to develop destructive cells that recognize self-tissues. Typically, through the "education" of developing immune cells, the organism inactivates potentially self-destructive cells, resulting in what is called self-tolerance. I proposed to explore the molecular mechanisms responsible for the induction and maintenance of tolerance. Our lab has developed a model of induced immune tolerance to skin and islet allografts utilizing a donor-specific transfusion of spleen cells and a brief course of anti-CD40L antibody. Because the difficulty in isolation of tolerant T cells from this system is ...


T Cell Immunity And Hiv-1 Replication In Vertically-Infected Infants And Children: A Dissertation, Zachary Aaron Scott May 2003

T Cell Immunity And Hiv-1 Replication In Vertically-Infected Infants And Children: A Dissertation, Zachary Aaron Scott

GSBS Dissertations and Theses

Virus-specific cellular immune responses have been shown to be important in the control of viral replication in several animal and human virus models. Cells of both the CD8+ and CD4+T cell lineages have been shown to play protective roles during viral infections by exerting effector functions that can kill infected host cells or inhibit the production and spread of infectious virions. The continued spread of HIV-1 infection throughout the world, as well as the lack of a prophylactic HIV-1 vaccine have generated much interest in HIV-specific cellular immune responses. Recent technical advances have yielded a tremendous increase in our ...


Long-Lived Memory T Lymphocyte Responses Following Hantavirus Infection: A Dissertation, Heather Lin Van Epps Jul 2001

Long-Lived Memory T Lymphocyte Responses Following Hantavirus Infection: A Dissertation, Heather Lin Van Epps

GSBS Dissertations and Theses

Hantaviruses are members of the virus family Bunyaviridaethat cause two potentially life-threatening diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (BPS). HFRS is caused by Old World hantaviruses that are endemic in many Asian and European countries. Infections with Old World hantaviruses can range in severity from asymptomatic to moderate or severe, depending primarily on the infecting serotype of virus. HPS is caused by New World hantaviruses in North and South America. New World hantaviruses are rarely asymptomatic and are severe in the majority of cases. These syndromes are distinct from one another in ...


The Ctl Memory Responses To Influenza A Viruses In Humans: A Dissertation, Julie Marie Jameson Nov 1999

The Ctl Memory Responses To Influenza A Viruses In Humans: A Dissertation, Julie Marie Jameson

GSBS Dissertations and Theses

Influenza A virus infections are a major cause of morbidity and mortality in the United States and throughout the world. The current vaccine elicits primarily a humoral response that is specific for the external glycoproteins hemagglutinin (HA) and neuraminidase (NA). However, these are the viral proteins that are most susceptible to antigenic shift and drift, and can evade the humoral response. Cytotoxic T lymphocytes (CTL) recognize and lyse virus-infected cells and are important in clearing influenza A virus infections. CTL can recognize epitopes on both the external glycoproteins and the more conserved internal viral proteins. This thesis investigates the hypothesis ...


Human T Cell Responses To Dengue Virus Infections: Cd8+Ctl And Acute Immunosuppression: A Dissertation, Anuja Mathew Jan 1999

Human T Cell Responses To Dengue Virus Infections: Cd8+Ctl And Acute Immunosuppression: A Dissertation, Anuja Mathew

GSBS Dissertations and Theses

There are four serotypes of dengue virus designated dengue 1, 2, 3 and 4 (D1, D2, D3 and D4) and epidemiological studies indicate that a severe complication of dengue virus infection - dengue hemorrhagic fever (DHF) is more likely to occur following a secondary infection. DHF is hypothesized to be immunologically mediated and may be triggered by virus-specific T cells. It is also likely that dengue virus-specific cytotoxic T lymphocytes (CTLs) are important for recovery from dengue virus infections. An analysis of the immune response during acute illness and when the patient has recovered from the infection (immune state) is therefore ...


The Virus-Specific Cd4+ T Cell Response During Acute Lymphocytic Choriomeningitis Virus Infection And Into Long Term Memory: A Dissertation, Steven Michael Varga Jan 1999

The Virus-Specific Cd4+ T Cell Response During Acute Lymphocytic Choriomeningitis Virus Infection And Into Long Term Memory: A Dissertation, Steven Michael Varga

GSBS Dissertations and Theses

CD4+ T cells play a central role in immunity. During virus infections, CD4+ T cells provide the necessary help for B cells to secrete anti-viral antibody and may act as effector cells themselves through the secretion of anti-viral cytokines such as IFN-γ and TNF-α. Recent studies in the lymphocytic choriomeningitis virus (LCMV) system have shown that CD4+ T cells are required to maintain the clearance of persistent viral infections as well as maintain virus-specific memory CD8+ cytotoxic T lymphocytes (CTL). Despite these important functions, surprisingly little information exists concerning the longevity, magnitude, and stability of the CD4+ T cell response ...


Cytotoxic T-Lymphocyte Responses During Acute Epstein-Barr Virus Infection, Brian L. Beaulieu May 1996

Cytotoxic T-Lymphocyte Responses During Acute Epstein-Barr Virus Infection, Brian L. Beaulieu

GSBS Dissertations and Theses

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which causes acute infectious mononucleosis and is etiologically associated with malignant lymphoproliferative disorders including Burkitt's lymphoma, nasopharyngeal carcinoma, B-cell lymphomas in immunocompromised hosts, Hodgkin's disease, T cell lymphomas, and smooth muscle tumors in allograft recipients. The medical significance of EBV is underscored by its potent growth transforming effects on human B-lymphocytes in-vitro and the potentially oncogenic consequences of infection in-vivo. The majority of EBV-associated malignancies occur in the setting of chronic infection and strong virus-specific humoral immunity, suggesting that cellular immunity is primarily responsible for preventing the outgrowth of EBV-transformed ...


Type-Specific Immunity In Hiv-1 Vertically Infected Infants, Cheryl A. Pikora Dec 1995

Type-Specific Immunity In Hiv-1 Vertically Infected Infants, Cheryl A. Pikora

GSBS Dissertations and Theses

High frequencies of CTL recognizing laboratory strains of HIV-1 are present in HIV-1 infected adults as early as preseroconversion. The presence of HIV-1 specific CTL during primary infection has been correlated with better control of early viremia and a more delayed onset of CD4 lymphocyte loss. Previous experiments in our laboratory have demonstrated that, unlike HIV-1 infected adults, the majority of vertically infected infants lack CTL which recognize laboratory strains of HIV-1 within the first year of life. ADCC antibody responses against laboratory strains of HIV-1 env gene products are also delayed until at least two years of age. As ...


The Role Of T Lymphocytes In The Hu-Pbmc-Scid Mouse Model Of Epstein-Barr Virus-Associated Lymphoproliferative Disease, Mary A. Cromwell Jun 1995

The Role Of T Lymphocytes In The Hu-Pbmc-Scid Mouse Model Of Epstein-Barr Virus-Associated Lymphoproliferative Disease, Mary A. Cromwell

GSBS Dissertations and Theses

Epstein-Barr virus (EBV) is associated with a spectrum of benign and malignant lymphoproliferative disorders, including acute infectious mononucleosis (IM), Burkitt's lymphoma (BL) and immunosuppression-associated B cell lymphoproliferative disease (LPD). Immunosurveillance mediated by virus-specific cytotoxic T lymphocytes is believed to protect immunocompetent hosts from EBV-associated lymphoma and LPD. Due to the lack of an adequate animal model, however, the precise immunologic mechanisms which provide this protection have not been directly demonstrated in vivo.

Human peripheral blood mononuclear cell-reconstituted C.B.-17-scid/scid mice (hu-PBMC-SCID mice) develop EBV-positive LPD following intraperitoneal injection of PBMC from EBV-seropositive donors. The SCID mouse ...


Role Of Recurrent Hydrophobic Residues In Catalyzing Helix Formation By T Cell-Presented Peptides: A Thesis, Shan Lu Dec 1990

Role Of Recurrent Hydrophobic Residues In Catalyzing Helix Formation By T Cell-Presented Peptides: A Thesis, Shan Lu

GSBS Dissertations and Theses

The overall objective of this study was to understand the mechanisms that control antigen processing and binding of peptides to major histocompatibility complex (MHC) molecules. Towards this goal I investigated (a) the structural features of T cell-presented peptides with a focus on the role of recurrent hydrophobic residues in catalysis of helix formation by these peptides and (b) the biochemical events that determine the fates of the invariant chain molecule (Ii) in its various post-translational processing pathways.

In the structural studies, I tested the hypothesis that the recurrence of hydrophobic amino acids in a polypeptide at positions falling in an ...