Date

2013

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

In this study we sought to understand both the role of interleukin-15 (IL-15) in normal lymphocyte homeostasis in rhesus macaques and also how increased IL-15 levels during simian immunodeficiency virus (SIV) infection contribute to lymphocyte homeostatic dysregulation and SIV pathogenesis. The common gamma chain (γc) cytokine IL-15 regulates the homeostasis and differentiation of CD8 and CD4 memory T cells (TM) and is required for the generation and maintenance of the major innate immune effector population, natural killer (NK) cells. However, the role of IL-15 maintaining these lymphocyte populations in vivo has not been fully characterized. To clarify the role of IL-15 in normal lymphocyte homeostasis, we administered healthy rhesus macaques (RM) doses of anti-IL-15 antibody (Ab) (N=15) or an IgG1 control Ab (N=10). Significantly, we observed that NK cells were almost completely depleted following anti-IL-15 Ab administration. Anti-IL-15 Ab treatment had no effect on central memory T cells (TCM) but resulted in an initial decline of CD4 and CD8 effector memory T cell (TEM) absolute numbers, but this decline was countered by the onset of TEM homeostatic proliferation, potentially induced by an increased sensitivity to IL-7 in the absence of IL-15 mediated signaling. Although the TEM homeostatic proliferative burst was associated with stabilization of absolute numbers in WB, TEM levels in the colon remained depleted and tissue expression of active caspase-3 was increased following anti-IL-15 Ab compared to IgG control Ab treatment. Moreover, microarray revealed that TEM expression profiles were dysregulated, with a signature indicating they were pre-apoptotic and turning over at an increased rate. Our studies thus reveal that ILxii 15 is necessary to maintain normal RM NK cell and effector memory T cell homeostasis in vivo. IL-15 has been implicated in the pathogenic hyperimmune activation that characterizes HIV/SIV infection, and its administration during acute SIV infection is associated with enhanced activation of CD4 memory T cells and higher post-peak viral replication. Thus, IL-15 activity might provide benefit to an HIV/SIV infected host by support of anti-viral T and NK cell effectors, and/or contribute to HIV/SIV pathogenesis by support of hyperimmune activation. To better understand the role of IL-15 in pathogenic SIV-infection, we treated 18 chronically SIVmac239 infected RM with 6 doses of the rhesusized anti-IL15 Ab, M111, (N=9) or IgG1 isotype control Ab (N=9) biweekly over a 10-week period. We next investigated the effect of anti-IL-15 Ab dosing on acute SIV-infection by administering 23 RM anti-IL-15 M111 Ab (N=15) or IgG1 isotype control Ab (N=8) before and up to 8 weeks post SIVmac239 infection. In both cohorts, anti-IL15 Ab was highly efficient at neutralizing IL-15 signaling in vivo and caused a near complete depletion of NK cells in the blood and tissues. Throughout anti- IL-15 Ab dosing, CD4 and CD8 TEM exhibited a high-turnover homeostasis, but longterm CD4 TEM absolute counts in blood and tissues remained unchanged compared to IgG control Ab treatment during both chronic and acute SIV-infection. Despite these notable changes to immune cell populations, viral replication rates and disease progression during chronic and acute SIV infection were comparable to those of control animals. These studies suggest that increased IL-15 levels during SIV-infection are not xiii primary drivers of disease progression and that NK cells do not play a significant role in either controlling SIV replication or promoting SIV pathogenesis.

Identifier

doi:10.6083/M49S1PC4

School

School of Medicine

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