Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

1-1-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Wayne Yokoyama

Abstract

Natural killer: NK) cells are hematopoietically derived immune cells of the lymphoid lineage. Their effector functions, including cytokine secretion and cytotoxicity, are controlled by the integration of signals received from both activating and inhibitory receptors. In a phenomenon known as "missing-self" recognition, NK cells eliminate self-tissues with aberrantly low or absent MHC class I surface expression, as is common in settings of viral infection and transformation, when these cells fail to engage the critical NK cell inhibitory receptors. Interestingly, NK cells that develop in an MHC class I-deficient environment are defective in natural killing and hyporesponsive to stimulation through their activation receptors, rather than hyperactive, as would be predicted by the missing-self hypothesis. Through contact between inhibitory receptors and their MHC class I ligands, NK cells are rendered both self-tolerant, as well as functionally competent. The process of MHC class I-dependent acquisition of NK cell function is termed "licensing." Herein we devised an experimental system of adoptive transfer, where unlicensed, splenic NK cells from MHC class I-deficient donors were transferred to wild-type: WT), MHC class I-sufficient hosts. Following transfer, donor NK cells expressing an inhibitory receptor specific for a cognate host-MHC class I molecule gained function, consistent with licensing of these cells. Further work demonstrated that normal MHC class I expression is required on both hematopoietic as well as non-hematopoietic tissues in order to produce the licensed phenotype. These results indicate that NK-intrinsic expression of MHC class I is not required for normal function, leading to the conclusion that contacts with MHC class I in the trans orientation are sufficient for licensing. Maintenance of the licensed phenotype and the potential for its reversal were examined following the inverse adoptive transfer of licensed, splenic WT NK cells into MHC class I-deficient hosts. We found that maintenance of the licensed phenotype also requires MHC class I expression by both hematopoietic and non-hematopoietic cells, and that loss of either of these contacts results in the loss of NK cell function, suggesting that licensing is reversible. Additionally, these results demonstrate that contacts with MHC class I molecules in the cis orientation are insufficient to maintain the licensed phenotype. Finally, in a second experimental model, parabiosis of MHC class I-deficient mice to WT partners, we explored the effect of bidirectional manipulation of MHC class I expression on NK cell function. Unexpectedly, we found a rapid and specific destruction of the spleen in the MHC class I-deficient partner, which appears to occur by a mechanism that is at least partially NK-dependent. These results suggest that factors not supplied in the context of adoptive transfer may contribute to the maintenance of function of WT NK cells, and that the NK-mediated survey of missing-self seems to be restricted to tissues of hematopoietic origin. In summary, these results demonstrate that NK cell licensing is both plastic and dynamic, fundamentally unique among the educational processes of immune lymphocytes. These results have important implications for the field NK immunotherapy, such as in the setting of peripheral NK cell adoptive transfer following bone marrow transplantation.

Comments

Permanent URL: http://dx.doi.org/10.7936/K72Z13HV

Download

Share

COinS