Date of Award

2014

Degree Type

Dissertation

Department

Chemistry

First Advisor

Zhou, Aimin

Subject Headings

Thymus -- Physiology, Ribonucleases, Homeostasis -- Immunology, Biochemistry

Abstract

RNase L is highly expressed in the spleen, thymus, and multiple immune cells, suggesting that it may play an important role in the immune system against microbes. Previous studies in the lab have shown that deficiency of RNase L results in enlarged thymuses in mice at young age. However, relatively little is known about its influence on the thymic development and adaptive immunogenicity. The present Ph.D. study focuses on investigating the role of RNase L in the thymic homeostasis and humoral immune responses, thereby gaining new insights into the molecular aspects in thymocyte development, maturation and adaptive immunity.By using RNase L gene knockout mice with C57BL/6 background, we found that RNase L deficient mice displayed severe homeostatic defect in the thymus, from birth until adolescence consistently. This homeostatic defect in the thymus was reflected by the increased population of BrdU positive cells, the enhanced growth rate and proliferation capacity in response to mitogens, and the elevated expression level of the pro-survival Bcl-2 protein while the expression of the pro-apoptotic Bax protein was suppressed. Further investigation indicated that wild type thymocytes were prone to be arrested in the G1/S phase of the cell cycle by p27Kip1. In addition, PTPH1, a protein tyrosine phosphatase, and its substrate VCP, a well-known cell cycle regulator, may be the target molecules of RNase L in preventing excessive cell proliferation by inhibiting cell cycle progression.To elucidate the effects of RNase L on immune responses, we immunized RNase L +/+ and -/- mice with T-dependent (TD) or T-independent (TI) antigens. Interestingly both spleen size and antibody production in TD or TI antigen immunized RNase L-/- mice were severely altered. A combination of GM-CSF, a hematopoietic growth factor facilitating both humoral and cellular mediated immunities, and the antigen in immunization, augmented TD antigen-directed immune responses in RNase L+/+ mice compared to that in RNase L-/- mice. PolyI:C,

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