Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

Summer 9-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Marco Colonna

Abstract

CD8+ T cells and NK cells are two effector cells of the mammalian immune system that rely on activating and inhibitory immunoreceptors to determine the outcome of an interaction with a target cell. An infected or transformed target cell can upregulate a variety of ligands that bind to activating receptors. Activating signals within an effector cell can then elicit responses that kill the target directly by lysing it or indirectly by secreting cytokines and chemokines that attract and activate other immune cells. In contrast, a healthy target cell can maintain expression of ligands for inhibitory receptors that restrain effector cell functions. NKG2A and KLRG1 are two examples of inhibitory immunoreceptors that are predominantly expressed on CD8+ T cells and NK cells. Both molecules are C-type lectin-like proteins that are encoded within the NK gene complex (NKC) in the mouse and human genomes. NKG2A forms a heterodimer with CD94 at the cell surface, while KLRG1 is expressed as a homodimer. Both surface molecules transmit inhibitory signals through two cytosolic immunoreceptor tyrosine-based inhibitory motifs (ITIM).

A variety of specific functions have been attributed to both NKG2A and KLRG1, although in vivo verification is mostly lacking. To this end, we have analyzed mice deficient in one or both molecules to unequivocally determine their functions in the context of the mammalian immune system. We have further chosen to analyze their activity in the context of viral infection, as this is a physiologically important mode of activation of both CD8+ T cells and NK cells. Specifically, we have studied the functions of NKG2A and KLRG1 in response to ectromelia virus (ECTV), an orthopoxvirus that is the mouse model of smallpox infection in humans. We found that NKG2A in particular is necessary to control the systemic spread of ECTV. Mice lacking NKG2A lack an effective CD8+ T cell response and are susceptible to infection. Surprisingly, this is a T cell-intrinsic defect and may be attributable to a role for NKG2A in preventing antigen-induced apoptosis of activated CD8+ T cells. Mice lacking both inhibitory receptors do not survive infection with ECTV, indicating that NKG2A and KLRG1 act in synergy to control this virus. We further analyzed the functions of KLRG1 by assessing its role in controlling a transient viral infection in the lungs, where KLRG1 appears to regulate the effector CD8+ T cell response to intranasal HSV-1 infection. Overall, these results illustrate novel in vivo roles for NKG2A and KLRG1 in the anti-viral response.

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K7KS6PKM

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