Novel roles for CD23, CTLA-4 and lipoproteins in human T cell function and differentiation
Newton, Amy Nicole
University of Kansas
Copyright held by the author.
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The differentiation of multipotent naïve T cells is influenced by the microenvironment. Cytokines, costimulatory proteins and other biological factors can tune this differentiation process, influencing cell fate. Controlling naïve T cell differentiation can guide the type of immune response elicited since each T cell subset has a specific function in the immune system. In this dissertation, I examine the participation of costimulatory molecules expressed on the surface of naïve CD4+ T cells in differentiation of these cells. I demonstrate that stimulation through the TCR and CTLA-4 directs naïve CD4+ T cell differentiation to regulatory T cells in the absence of exogenous cytokines. I evaluate how combined stimuli influence differentiation and function in T cells. Combined stimulation through CTLA-4 and CD28 (CD3+CD28+CTLA-4) results in distinct functional outcomes from combined stimulation through CTLA-4 and ICAM-1 (CD3+ICAM-1+CTLA-4) or alternatively, ICAM-1 and CD28 (CD3+CD28+ICAM-1). Differentiation to Th1, Th2 or Treg cells has been evaluated in our previous studies. In this dissertation, I extend these studies by examining whether costimulation in the absence of exogenous cytokines can support Th17 differentiation. I found that costimulation through ICAM-1, CD28, LFA-1, or CTLA-4 did not activate naïve CD4+ T cells to differentiate to Th17 cells. I also evaluated how the low affinity IgE receptor, CD23, expressed on T cells participates in naïve T cell differentiation and mature T cell function. CD23 functions as a negative regulator of Th2 responses by inhibiting differentiation of naïve T cells to Th2 cells and enhancing activation of Th1 cells in mature T cells. Next, I examined how lipoproteins relevant to atherosclerosis may guide differentiation of naïve CD4+ T cells. Consistent with their known roles in promoting or inhibiting atherosclerosis, oxLDL activates differentiation to Th1 cells whereas HDL inhibits T cell proliferation and viability. Different responses by naïve T cells to these lipoproteins may have direct implications in how atherosclerosis is exacerbated or attenuated during disease. Finally, I explore whether autoimmunity is involved in a mouse model of emphysema. I demonstrate that T cells adoptively transferred emphysema to naïve, immunodeficient mice, supporting a role for autoimmunity in an elastase-induced model. Peptide therapy targeting the interactions between ICAM-1 and LFA-1 was able to reduce severity of emphysema as well.
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