Browsing by Subject "CD4"

Now showing 1 - 4 of 4
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    CD4+ T cell differentiation and help to B cells
    (2019-02) Kotov, Jessica
    Vaccines save 2.5 million lives per year. Vaccine efficacy is largely dependent on the successful generation of antibodies by B cells for the elimination of pathogens like the influenza virus. T follicular helper (Tfh) cells are a type of CD4+ T cell that provides critical help to B cells for this process. My thesis research involves studying factors that promote Tfh cell formation and therefore B cell responses. This research is significant because it will provide better understanding of how Tfh cells are generated, which can be implemented during vaccine design. Using an approach to track both polyclonal antigen- specific CD4+ T and B cells within the same mouse after Complete Freund’s Adjuvant immunization, we found that the expression of BCOR protein in CD4+ T cells was critical for optimal Tfh formation. Reduced Tfh development as a result of BCOR absence also led to reduced germinal center B cell and antibody-secreting plasma cell formation. Thus, BCOR plays a critical role in promoting Tfh differentiation and B cell responses. The role of BCOR in CD4+ T cell differentiation was also examined after infection of mice with the extracellular pathogen Streptococcus pyogenes (Group A Streptococcus). In this context, BCOR enhanced the development of another CD4+ T cell type called T helper 17 (Th17) cells. Th17 cells promote protection by secreting cytokines, like IL-17A, that drive trafficking of neutrophils to the site of infection to kill bacteria. Identifying the drivers of Th17 cells will inform the development of a Th17- focused Streptococcus pyogenes vaccine for humans, which is currently unavailable. Because the efficacy of most vaccines is based on the process by which CD4+ T cells stimulate antibody responses, we wanted to better understand the role of different CD4+ T cell types on the B cell response. Tfh cells, in addition to Th1 and Th17 cells, were found to contribute to the production of early antibody-secreting B cells. This work provides insight into how non-Tfh cells also contribute to the B cell response, which is understudied in the field of B cell biology. Better understanding the process of CD4+ T cell help for generating antibody-secreting B cells is critical for producing efficacious vaccines.
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    Eliciting Th1 effector functions: A mechanism and role for innate amplification of the Th1 response during infection
    (2014-06) O'Donnell, Hope
    Innate and adaptive immunity have classically been considered as two distinct categories of cells and responses. Recently, however, an increasing appreciation for the dynamic interactions between these responses has developed. In this dissertation, this overlap is explored in the context of Th1 CD4 T cell production of IFN-γ (interferon-gamma) in response to innate stimuli. In particular, we first asked what triggers innate stimulation of Th1 cells, examining multiple ligands, infections and time points to show that this response occurred within broad contexts of intracellular infection. We then asked how T cells are able to recognize innate stimuli, focusing on whether the T cell intrinsic response relied upon direct LPS (lipopolysaccharide) recognition or indirect recognition of secondary signals. T cell intrinsic requirements were examined in mixed bone marrow chimeras that allowed T cells to be compared within the same environment. Upon demonstrating that the innate Th1 cell response required IL-18 (interleukin-18) receptor signaling, we next explored how T cell extrinsic PRRs (pattern recognition receptors) elicit effector functions through IL-18 secretion. Here, we showed a dual requirement for both TLR4 (toll-like receptor 4) and inflammasome pathways after LPS stimulation during Salmonella infection. The convergence of these pathways was required for increased IL-18 secretion, suggesting a dual level of control in production of such a proinflammatory cytokine. Finally, we asked whether the innate stimulation of Th1 cells is a required response pathway during clearance of Salmonella. Using Lck-cre x MyD88-loxP crossed mice, we demonstrated a deficiency in bacterial clearance in the absence of the signaling molecule MyD88 within T cells, which impairs the ability of Th1 cells to respond to IL-18, but not classical antigen stimulation. Together, this data suggests that the Th1 cell response utilizes a pathway of innate stimulation to amplify IFN-γ production under situations of severe inflammation, in which the classical adaptive response pathway may not be sufficient to mediate a strong and rapid response. Future work may explore additional infectious contexts, other CD4 T cell subsets, memory responses, and circumstances of immunopathology.
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    Examining Helper T-cell Recovery After Sepsis
    (2015-08) Cabrera-Perez, Javier
    Sepsis strikes 750,000 Americans every year with ~ 210,000 of these patients dying – far more than the number of deaths from prostate cancer, breast cancer, and AIDS combined. Some of these deaths occur during the acute, inflammatory stages of sepsis, but ~70% of these patients survive the initial infection, only to perish due to hospital-acquired infections. Most sepsis research has focused on understanding the acute, inflammatory stage of sepsis, but the increased susceptibility to secondary infections has led clinicians and researchers to believe that the chronic stage of sepsis is important and is characterized by immunosuppression. CD4 T-cells, essential for coordinating immune responses to opportunistic pathogens, are severely depleted during the acute stage of sepsis, but gradually recover throughout the immunosuppressive phase of sepsis. Despite the well-characterized immune cell apoptosis during sepsis, the impact of sepsis on protective T-cell responses (especially CD4 T-cells) against secondary pathogen challenge remains poorly understood. This dissertation presents a previously unappreciated mechanism of CD4 T-cell impairment during the immunosuppressive stage of sepsis. In the present study, we have studied sepsis immunosuppression by using Class II major histocompatibility complex tetramers to track endogenous, antigen specific CD4 T-cells, in order to examine a hypothesis: that the uneven recovery of the Ag-specific CD4 T-cell repertoire contributes to the alarming rate of infections in sepsis survivors. In addition, we have examined the impact of enteric microbial populations in the recovery of CD4 T-cells after sepsis. The results described present a previously unappreciated mechanism of CD4 T-cell impairment during the immunosuppressive stage of sepsis.
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    Roles of CD28, Inducible Costimulator, and the Interleukin-2 receptor in helper T cell memory formation.
    (2012-08) Pagan, Antonio Jose
    Numerous studies have suggested that CD28, Inducible Costimulator (ICOS), and Interleukin-2 receptor (IL-2R) signals shape the size and composition of the helper T cell memory pool, but the extent to which these signals regulate specific aspects of memory formation and the precise mechanisms of these processes remain unclear. To address this question, we used a sensitive peptide:Major Histocompatibility Complex II (p:MHCII) tetramer and magnetic bead-based enrichment method to track p:MHCII-specific helper T cells in mice throughout the course of an immune response. We found that CD28, ICOS, and the IL-2R each control unique aspects of helper T cell memory formation. The major defect in CD28-deficient T cells was a failure to sustain the proliferation of effector T cells and not a defect in memory formation per se; CD28-deficient T cells produced memory cells proportionate to the number of effectors present at the peak of the response. Our findings suggest that CD28 mediates this process by enhancing TCR-dependent NFκB signaling independently of the two CD28 cytoplasmic tail sequences previously implicated in clonal expansion. In contrast, ICOS or IL-2R deficiency did not grossly reduce the overall size of the effector or memory cell populations. Instead, they controlled the generation of two distinct subsets of memory T cells from effector cells that were present several days after infection. T-bethigh T helper type-1 effector memory (Th1em) cells were generated in an IL-2R-dependent fashion. In contrast, T-betlow CC chemokine receptor 7 (CCR7)+ CXC cheomokine receptor 5 (CXCR5)+ central memory T (Tcm) cells were formed in a Bcl6- and ICOS-dependent manner from T follicular helper (Tfh) effector cells. Thus, CD28, ICOS, and IL-2R regulate distinct aspects of helper T cell memory formation.