Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Wayne Yokoyama

Abstract

Natural killer: NK) cells are innate immune lymphocytes that react to cells lacking self-MHC: major histocompatibility complex) class I molecules, such as transformed or virally infected host cells and allogeneic bone marrow. This reactivity is mediated by inhibitory receptors for MHC class I that block the ability of activation receptors to stimulate NK cells. Since many NK cells lack receptors that recognize self-MHC, the inhibitory receptors also mediate a second function, termed NK cell licensing, to protect against autoreactivity. To become licensed, i.e. functionally competent to be triggered through its activation receptors, an NK cell must engage host MHC class I via at least one of its MHC class I-specific inhibitory receptors, which in mice belong to the Ly49 family of receptors. However, many properties of this process remain unclear. To explore potential determinants of NK cell licensing on a single Ly49 receptor, we have investigated the relative licensing impacts of the b, d, k, q, r, and s H2 haplotypes on Ly49A+ NK cells. In ex vivo stimulation assays, some Ly49A-MHC class I haplotype combinations produced an intermediate licensing phenotype, indicating that licensing is not a binary phenomenon. Comparisons of these data with soluble Ly49A tetramer binding assays indicate that licensing is essentially analog but is saturated by moderate-binding MHC class I ligands. Interestingly, licensing exhibited a strong inverse correlation with Ly49A surface accessibility, a measure of cis engagement of Ly49A with MHC class I expressed on the same cell. Finally, Ly49A-mediated effector inhibition was found to be more sensitive to MHC class I engagement than licensing of Ly49A+ NK cells, suggesting that licensing establishes a margin of safety against NK cell autoreactivity.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7F769K9

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