Browsing by Subject "Immunologic Memory"
Now showing 1 - 4 of 4
- Results Per Page
- Sort Options
Item The Effects of Imatinib Mesylate on Antigen-Specific Cd8+ T Cell Responses(2006-12-20) Sinai, Parisa; Forman, JamesImatinib mesylate (IM) is a chemical compound designed to inhibit the constitutive tyrosine kinase activity of the Bcr-Abl oncogene in Chronic Myelogenous Leukemia (CML). While IM is very potent in treating CML, little is understood concerning the effects of IM on the immune response. In this study, I have examined the influence of IM on antigen specific CD8 T cells. Mature OT-1 TCR transgenic T cells were transferred into B6.Thy1.1 recipients. This transfer was followed by an infection with Listeria monocytogenes (LM) expressing the cognate epitope OVA 257-264 (LM-OVA) to assess whether IM affects the specific CD8 T cell response generated to this intracellular pathogen. In vitro studies revealed that IM had no effect on proliferation, apoptosis, or IFN-gamma secretion of na?or memory OT-1 T cells at doses of =5muM, although at higher doses inhibition was observed. Adoptive transfer and in vivo infection studies demonstrated that in the presence of IM the primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered as measured by OT-1 T cell percentages in spleen and blood, their expression of IFN-gamma and their proliferation. However, IM influenced the primary OT-1 response by decreasing the expression of the IL-7Ralpha memory marker on OT-1 cells. IM treatment for >28 days resulted in a decreased percentage of OT-1 memory T cells before recall in blood. Furthermore, the response of memory OT-1 cells after LM-OVA rechallenge was diminished as measured by OT-1 T cell percentages in blood. In addition, IM treatment reduced the expression of IL-7Ralpha , a receptor required for memory cell survival, on effector and memory OT-1 cells. The function of memory OT-1 cells as measured by IFN-gamma expression was unaltered as was their proliferation as measured by incorporation of Brdu. Infection assays revealed that clearance of LM-OVA by memory mice is not altered by IM. In addition, the in vivo proliferation of memory OT-1 cells was not altered by IM. While IM did not alter the percentage of CD4 T cells in spleen and blood, IFN-gamma expression by CD4 T cells after recall was decreased. Together, these data demonstrate that IM reduces the number of OT-1 cells following a secondary challenge to an LM-OVA infection, and this may be a result of decreased IL-7Ralpha expression on effector and memory OT-1 cells.Item Preferential Regulatory T-Cell Generation from Memory CD4+ T-Cells Is Deficient During Acute Exacerbation of Multiple Sclerosis(2014-06-11) Mohiuddin, Imran Hafiz; Niederkorn, Jerry Y.; Karakndikar, Nitin J.; Mohan, Chandra; Gruchalla, Rebecca S.Multiple sclerosis (MS) is an immune-mediated disease with reported defects in thymic T-cell output. Thymically-derived natural regulatory T-cells (nTregs) play a vital role in suppressing autoimmune responses. We have previously shown that, in humans, all activated T-cells attain transient FOXP3 expression that correlates with suppressive ability. In fact, peripheral generation of induced Tregs (iTregs) is likely the dominant source of regulatory cells in healthy adults and even more so in MS patients. Through the use of a sensitive flow-based suppression assay, we observed that memory and naïve CD4+CD25-FOXP3- T-cells both developed regulatory ability subsequent to a variety of activating stimuli. This suppressive ability was greater than that observed in nTregs and not explained by exhaustion of nutrients or competition for APCs. While blockade of activation using anti-IL-2, CTLA-4 Ig, anti-TGF-β, indomethacin or cyclosporin A did not affect iTreg generation, methotrexate preempted the induction of regulatory ability. Moreover, irradiation of iTregs also abrogated regulatory function. Interestingly, memory-derived CD25+ iTregs displayed significantly greater activation-induced FOXP3 induction compared to naïve counterparts, and exhibited significantly enhanced suppressive function per cell. Furthermore, the CD25- fraction of activated memory-derived iTregs also demonstrated regulatory function not observed in naïve counterparts. In particular, this induced regulatory population was present in both healthy controls and quiescent MS patients, but deficient during MS acute exacerbation. These studies suggest that iTreg development and function may vary dependent on precursor origin, and that clinical recovery from exacerbation to ix quiescence in MS is associated with a restoration of function in memory-derived CD4+CD25-FOXP3- Tregs.Item Reciprocal Regulation of CD4+ and CD8+ T Lymphocyte Effector and Memory Fates by Interleukin 12 and Type 1 Interferon(2009-06-18) Ramos, Hilario Jose; Farrar, J. DavidCytokine signaling networks play an important role in bridging the innate and adaptive immune responses. For example, the innate cytokines Interleukin-12 (IL-12) and type I interferon (IFN-a/b) are induced to high levels by intracellular bacterial and viral infections and have been shown to promote adaptive T lymphocyte responses to infection. While the role for IL-12 on the development of T lymphocyte effector responses has been well characterized, the exact role for IFN-a/b on these responses has been controversial. Therefore, the present study set forth to characterize the distinct roles for IL-12 and IFN-a/b on the development of effector and memory responses in human CD4+ and CD8+ T cells. My work has found that IL-12 drives the development of effector CD4+ and CD8+ T cells. In contrast, IFN-a/b was incapable of promoting these responses and this was due to a difference in the kinetics of activation of two downstream transcription factors STAT4 and T-bet. Further examination of CD8+ T cells revealed a distinct role for IFN-a/b in the development of a population of central memory T cells (TCM). Alternatively, IL-12 drove the development of effector memory cells (TEM). The variegated development of TCM and TEM was dictated by differential cytokine receptor expression and further, the strength of primary T cell receptor (TCR) activation determined the responsiveness to cytokine polarization. Finally, these studies uncovered a novel role for CD8+ T cell licensing of CTL activity through the costimulatory CD27/CD70 pathway. Therefore, taken together, these findings support a novel model in which TCR activation and costimulation act to shape the ability for IL-12 and IFN-a/b to differentially program the development of distinct classes of effector and memory CD8+ T lymphocytes. These studies have direct bearing on the design and development of effective therapeutics and vaccines and demonstrate a new understanding on the modulation of the adaptive immune response to intracellular infection.Item Regulation of Effector and Memory Development of Human CD4+ T Cells by Interleukin 12 and Type I Interferon(2009-01-09) Davis, Ann Marie; Farrar, J. DavidInnate cytokines induced at the onset of infection regulate the development of adaptive immune responses such as CD4+ T helper cell development. For instance, the innate cytokines interleukin 12 (IL-12) and type I interferon (IFN-alpha/beta) are produced in response to intracellular bacterial and viral infections. While the effects of IL-12 on CD4+ T cell differentiation are relatively well-understood, the role of IFN-alpha/beta, despite extensive study, has remained controversial. The present work seeks to clarify the effects of IFN-alpha/beta on CD4+ T cell development, effector functions, and memory generation. Previous reports had suggested that IFN-alpha, like IL-12, could promote Th1 development in human CD4+ T cells. However, my work demonstrates that IFN-alpha is insufficient to induce Th1 differentiation because of an inability to maintain stable STAT4 phosphorylation or T-bet expression. Furthermore, IL-12, but not IFN-alpha, induces the secretion of IFN-gamma and TNF-alpha from human CD4+ T cells. These two cytokines, in addition to promoting bacterial clearance, can directly participate in antiviral immunity via a signaling pathway which involves the type I IFN receptor. Finally, a combination of IL-12 and IFN-alpha influences memory CD4+ T cell function by strongly inducing IL-2 secretion from a subset of cells in a T-bet-independent manner. These IL-2-producing cells demonstrate both phenotypic and functional characteristics of long-lived and pluripotent central memory. Taken together, these data provide a new understanding of the role of innate cytokines in shaping adaptive CD4+ T cell responses. Given the numerous medical uses of IFN-alpha/beta, these findings could have a broad impact on the design of vaccines and antiviral therapeutics.