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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 ...


Regulation Of Type Ii Responses In Lung Fibrosis And Systemic Autoimmunity: A Dissertation, Tia Bumpus Brodeur Apr 2014

Regulation Of Type Ii Responses In Lung Fibrosis And Systemic Autoimmunity: A Dissertation, Tia Bumpus Brodeur

GSBS Dissertations and Theses

Preclinical models of lupus indicate that T cell-B cell collaboration drives antinuclear antibody (ANA) production and sustains T cell activation. Autoreactive B lymphocytes are present in the normal repertoire but persist as ignorant or anergic cells. Mechanisms that normally limit T cell activation of autoreactive B cells remain incompletely resolved, but potentially include the absence of autoreactive effector T cell subsets and/or the presence of autoAgspecific regulatory T cells (Tregs). Several studies have addressed this issue by using experimental systems dependent on transgenic autoreactive B cells, but much less is known about the activation of autoreactive B cells present ...


Molecular Studies Of T Cell Recognition And Cross-Reactivity: A Dissertation, Zu T. Shen Jul 2012

Molecular Studies Of T Cell Recognition And Cross-Reactivity: A Dissertation, Zu T. Shen

GSBS Dissertations and Theses

Intracellular pathogens are recognized by a specialized subset of lymphocytes known as CD8+ T cells. Pathogen recognition by CD8+ T cells occurs through binding of T cell receptors (TCR) to processed antigens in complex with major histocompatibility complex (MHC) class I proteins. TCR engagement of antigens in complex with MHC class I typically lead to cytotoxic CD8+ T cell responses, which result in pathogen clearance. Due to the large number of foreign antigens that might be encountered by any given host a diverse repertoire of TCRs must be available for immune recognition. The main source of TCR diversity is generated ...


On The Source Of Peptides For Major Histocompatibility Class I Antigen Presentation: A Dissertation, Diego José Farfán Arribas Apr 2012

On The Source Of Peptides For Major Histocompatibility Class I Antigen Presentation: A Dissertation, Diego José Farfán Arribas

GSBS Dissertations and Theses

Peptides generated from cellular protein degradation via the ubiquitin-proteasome pathway are presented on MHC class I as a means for the immune system to monitor polypeptides being synthesized by cells. For CD8 + T cells to prevent the spread of an incipient infection, it appears essential they should be able to sense foreign polypeptides being synthesized as soon as possible. A prompt detection of viral proteins is of great importance for the success of an adaptive immune response. Defective ribosomal products (DRiPs) have been postulated as a preferential source which would allow for a rapid presentation of peptides derived from the ...


The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin Mar 2012

The Role Of Heterologous Immunity In Mediating Natural Resistance To Infection In Human Subjects: A Dissertation, Levi B. Watkin

GSBS Dissertations and Theses

Heterologous immunity is a mechanism by which immunological memory within an individual, developed in response to a previous infection, plays a role in the immune response to a subsequent unrelated infection. In murine studies, heterologous immunity facilitated by cross-reactive CD8 T-cell responses can mediate either beneficial (protective immunity) or detrimental effects (e.g. enhanced lung and adipose immunopathology and enhanced viral titers) (Selin et al., 1998; Chen et al., 2001; Welsh and Selin, 2002; Nie et al., 2010; Welsh et al., 2010). Protective heterologous immunity results in enhanced clearance of virus during a subsequent infection with an unrelated pathogen. Such ...


Primary And Secondary Immune Responses During Sequential West Nile Virus And Japanese Encephalitis Virus Infections: A Dissertation, Derek W. Trobaugh Feb 2012

Primary And Secondary Immune Responses During Sequential West Nile Virus And Japanese Encephalitis Virus Infections: A Dissertation, Derek W. Trobaugh

GSBS Dissertations and Theses

Japanese encephalitis virus (JEV) and West Nile virus (WNV) are closely related Flaviviruses that are important arthropod-borne human pathogens. Both of these viruses can cause encephalitis with significant morbidity and mortality after infection. Flaviviruses co-circulate in many areas of the world, which raises the risk for sequential infection between heterologous viruses. Sequential infection between dengue virus serotypes can lead to cross-protection, but in some cases, it leads to a severe outcome, dengue hemorrhagic fever. Previous work in hamsters and non-human primates demonstrated that prior JEV immunity protects against a lethal WNV infection. However, the ability of prior WNV immunity to ...


Cd8+ T Cell Serotype-Cross-Reactivity Is A Predominant Feature Of Dengue Virus Infections In Humans: A Dissertation, Heather L. Friberg-Robertson Nov 2010

Cd8+ T Cell Serotype-Cross-Reactivity Is A Predominant Feature Of Dengue Virus Infections In Humans: A Dissertation, Heather L. Friberg-Robertson

GSBS Dissertations and Theses

The four serotypes of dengue virus (DENV 1-4) have a significant and growing impact on global health. Dengue disease encompasses a wide range of clinical symptoms, usually presenting as an uncomplicated febrile illness lasting 5-7 days; however, a small percentage of infections are associated with plasma leakage and bleeding tendency (called dengue hemorrhagic fever, DHF), which can result in shock. Epidemiological studies indicate that severe dengue disease most often occurs during secondary heterotypic DENV infection. Additionally, plasma leakage (the hallmark of DHF) coincides with defervescence and viral clearance, suggesting that severe disease arises from the immune response to infection rather ...


Regulation Of Early T Cell Activation By Tnf Superfamily Members Tnf And Fasl: A Dissertation, Bhavana Priyadharshini Sep 2010

Regulation Of Early T Cell Activation By Tnf Superfamily Members Tnf And Fasl: A Dissertation, Bhavana Priyadharshini

GSBS Dissertations and Theses

The instructive signals received by T cells during the programming stages of activation will determine the fate of effector and memory populations generated during an immune response. Members of the tumor necrosis factor (TNF) superfamily play an essential role in influencing numerous aspects of T cell adaptive immune responses including cell activation, differentiation, proliferation, survival, and apoptosis. My thesis dissertation describes the involvement of two such members of the TNF superfamily, TNF and FasL, and their influence on the fate of T cells early during responses to viral infections and to the induction of transplantation tolerance.

TNF is a pleiotropic ...


Regulation Of Immune Pathogenesis By Antigen-Specific Cd8 T Cells Following Sequential Heterologous Infections: A Dissertation, Alex T. Chen Apr 2010

Regulation Of Immune Pathogenesis By Antigen-Specific Cd8 T Cells Following Sequential Heterologous Infections: A Dissertation, Alex T. Chen

GSBS Dissertations and Theses

Previously, our lab demonstrated that heterologous immunity could result in either gain or loss of protective immunity and alteration in immune pathology following infection by a second un-related pathogen. One of the prototypical models to study T cell-mediated heterologous immunity involves two distantly related arenaviruses, namely lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV). Each virus encodes a cross-reactive CD8 epitope that has six out of eight in amino acid (aa) similarity with respect to its counterpart at the position 205-212 of the nucleoprotein (NP205). Heterologous challenge between LCMV and PV results in 1) expansion of the cross-reactive NP205-specific CD8 ...


Sensitization Of Cd8 T Cells During Acute Viral Infections Impacts Bystander And Latecomer Cd8 T Cell Responses : A Dissertation, Heather D. Marshall Oct 2009

Sensitization Of Cd8 T Cells During Acute Viral Infections Impacts Bystander And Latecomer Cd8 T Cell Responses : A Dissertation, Heather D. Marshall

GSBS Dissertations and Theses

Many virus infections induce a transient state of immune suppression in the infected host. Virus-induced T cell suppression can be caused by T cell activation-induced cell death (AICD), dendritic cell (DC) apoptosis, DC dysfunction, and/or the enhanced expression of immune-suppressive cytokines. It has been previously demonstrated that naïve bystander CD8 T cells derived from hosts experiencing an acute virus-specific T cell response underwent AICD when polyclonally activated by anti-CD3 in vitro (Zarozinski et al., 2000). Susceptibility of naïve bystander T cells to AICD could prevent the development of a new T cell response during an ongoing immune response, and ...


The Role Of Tec Family Kinases In Innate T Cell Development And Function: A Dissertation, Martin Felices Jun 2008

The Role Of Tec Family Kinases In Innate T Cell Development And Function: A Dissertation, Martin Felices

GSBS Dissertations and Theses

The Tec family kinases Itk and Rlk have been previously shown to have an important role in signaling downstream of the T cell receptor [TCR]. Almost all of the work done in the past on these two kinases looked at their role in conventional αβ T cells, specifically CD4+ T cells. These studies demonstrated functions for Itk [primarily] and Rlk in T cell development, activation, and differentiation. However, despite the wealth of knowledge on conventional CD4+ T cells, prior to the work presented here little to no studies addressed the role of Tec family kinases on CD8+ or innate T ...


Cross-Reactive Memory Cd4+ And Cd8+ T Cells Alter The Immune Response To Heterologous Secondary Dengue Virus Infections In Mice: A Dissertation, Coreen Michele Beaumier Feb 2008

Cross-Reactive Memory Cd4+ And Cd8+ T Cells Alter The Immune Response To Heterologous Secondary Dengue Virus Infections In Mice: A Dissertation, Coreen Michele Beaumier

GSBS Dissertations and Theses

Dengue virus (DENV) infects 50-100 million people worldwide every year and is the causative agent of dengue fever (DF) and the more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). There are four genetically and immunologically distinct DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). Evidence suggests that an increased risk for DHF/DSS during secondary infection with a heterologous DENV serotype is due to an immunopathological response mediated by serotype-cross-reactive memory T cells from the primary infection. Furthermore, epidemiological studies have shown that the sequence of infection with different DENV serotypes affects disease severity. Though much has been learned ...


Attrition Of Cd8 T Cells During The Early Stages Of Viral Infections: A Dissertation, Kapil Bahl Jan 2008

Attrition Of Cd8 T Cells During The Early Stages Of Viral Infections: A Dissertation, Kapil Bahl

GSBS Dissertations and Theses

Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type 1 IFN-dependent loss of most memory (CD44hi) and some naïve (CD44lo) CD8 T cells immediately preceding the development of the antiviral T cell response at days 2-4 following lymphocytic choriomeningitis virus (LCMV) infection. In this thesis, I will examine additional mechanisms involved in the early attrition of CD8 T cells and evaluate whether antigen-specific and non-specific CD8 T cells are equally susceptible. Lastly, I will examine whether the early attrition of CD8 T cells contributes to the generation of an ...


The Role Of Cd40 In NaïVe And Memory Cd8+ T Cell Responses: A Dissertation, Maria Genevieve H. Hernandez May 2007

The Role Of Cd40 In NaïVe And Memory Cd8+ T Cell Responses: A Dissertation, Maria Genevieve H. Hernandez

GSBS Dissertations and Theses

Stimulation of CD40 on APCs through CD40L expressed on helper CD4+ T cells activates and “licenses” the APCs to prime CD8+ T cell responses. While other stimuli, such as TLR agonists, can also activate APCs, it is unclear to what extent they can replace the signals provided by CD40-CD40L interactions. In this study, we used an adoptive transfer system to re-examine the role of CD40 in the priming of naïve CD8+ T cells. We find an approximately 50% reduction in expansion and cytokine production of TCR-transgenic T cells in the absence of CD40 on all APCs, and on dendritic cells ...


Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam Oct 2006

Serotype Cross-Reactive Cd8+ T Cell Response To Heterologous Secondary Dengue Virus Infections In Humans: A Dissertation, Hema Sundara Bashyam

GSBS Dissertations and Theses

The generation of memory T cells following primary exposure to a pathogen is a critical feature of the vertebrate immune system which has evolved as a protective mechanism in order to defend the host against repeated assaults by the patnogen. Memory T cells are long-lived, undergo rapid proliferation upon re-activation, mediate a robust secondary response and clear the pathogen much more efficiently. These aspects have made the generation of memory T cells an attractive goal for the production of both prophylactic and therapeutic vaccines. However, the degeneracy of the T cell receptor, whereby a given T cell recognizes more than ...


Cross-Reactive Cd8 T Cell Responses And Heterologous Immunity During Acute Epstein-Barr Virus Infection: A Dissertation, Shalyn Catherine Clute Jul 2005

Cross-Reactive Cd8 T Cell Responses And Heterologous Immunity During Acute Epstein-Barr Virus Infection: A Dissertation, Shalyn Catherine Clute

GSBS Dissertations and Theses

A person is exposed to many pathogens throughout their lifetime, and with the resolution of each infection, there remains a pool of pathogen-specific immune cells that protect that person from re-infection with the same pathogen. However, there is a great deal of evidence to suggest that the pool of pathogen-specific memory cells can also participate in the immune response to future infections with unrelated pathogens. Many believe T cells to be cross-reactive in nature because of their interaction with self antigens during development in the thymus and their interaction with foreign antigens once in the periphery. There are many features ...


The Role Of Itk In T Cell Development: A Dissertation, Julie Ann Lucas Jan 2005

The Role Of Itk In T Cell Development: A Dissertation, Julie Ann Lucas

GSBS Dissertations and Theses

Itk is a member of the Tec family of non-receptor tyrosine kinases. It is expressed in T cells, NK cells, and mast cells. The purpose of this study was to determine the role of Itk in T cell development. Previous work from our lab and others has demonstrated that Itk is involved in signaling downstream of the T cell receptor and initial analysis of Itk-deficient mice revealed that these mice had some defects in T cell development. There are two stages of T cell development, the pre-T cell stage and the CD4+ CD8+ double positive stage, at which signals downstream ...


Macrophages Directly Prime NaïVe Cd8+ T Cells: A Dissertation, Lu-Ann M. Pozzi Sep 2004

Macrophages Directly Prime NaïVe Cd8+ T Cells: A Dissertation, Lu-Ann M. Pozzi

GSBS Dissertations and Theses

Professional antigen presenting cells (APCs) represent an important link between the innate and adaptive immune system. Macrophages (MΦs) and dendritic cells (DCs) serve as sentinels in the periphery collecting samples from their environment and processing this information. These cells then present antigenic fragments to T cells in the context of self-MHC molecules. Although a clear role for both of these APCs in the stimulation of already activated or memory T cells has been established, the ability of MΦs to activate naive T cells is still unknown. In this thesis the ability of bone marrow-derived MΦs and DCs to prime naive ...


The Role Of Itk And Rlk In Cd8+ T Cell Development And Function: A Dissertation, Luana O. Atherly Jul 2004

The Role Of Itk And Rlk In Cd8+ T Cell Development And Function: A Dissertation, Luana O. Atherly

GSBS Dissertations and Theses

Itk and Rlk are members of the Tec kinase family of non-receptor protein tyrosine kinases that are preferentially expressed in T cells. Numerous previous studies have demonstrated that these proteins play an important a role in the regulation of signalling processes downstream of TCR activation in CD4+ T cells, particularly in the phosphorylation of PLCγl. In addition, Itk and Rlk have both been shown to be important for CD4+ T cell development, differentiation, function and homeostasis following TCR activation. In the absence of Itk and Rlk, CD8+ SP thymocytes and T cells develop a memory/previously activated phenotypic profile, however ...


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 ...


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 ...


Activation And Role Of Memory Cd8 T Cells In Heterologous Antiviral Immunity And Immunopathology In The Lung: A Dissertation, Hong Chen Dec 2002

Activation And Role Of Memory Cd8 T Cells In Heterologous Antiviral Immunity And Immunopathology In The Lung: A Dissertation, Hong Chen

GSBS Dissertations and Theses

Each individual experiences many sequential infections throughout the lifetime. An increasing body of work indicates that prior exposure to unrelated pathogens can greatly alter the disease course during a later infection. This can be a consequence of a phenomenon known as heterologous immunity. Most viruses invade the host through the mucosa of a variety of organs and tissues. Using the intranasal mucosal route of infection, the thesis focused on studying modulation of lymphocytic choriomeningitis virus (LCMV)-specific memory CD8 T cells upon respiratory vaccinia virus (VV) infection and the role of these memory CD8 T cells in heterologous immunity against ...


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 ...


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 ...