Date of Award

Spring 5-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Innate lymphoid cells (ILCs) are a recently discovered lineage of professional cytokine-producing cells that strikingly mirror T cells in transcriptional circuitry and effector functions, but derive from distinct progenitors and do not express recombined antigen-specific receptors. These cells include natural killer (NK) cells, which parallel cytotoxic CD8+ T cells, and three additional classes of ILCs enriched at mucosal surfaces that generate signature cytokines reminiscent of polarized CD4+ helper T cells subsets, called ILC1, ILC2, and ILC3. As ILCs have been implicated in the pathogenesis of colitis, cancer, allergy, and autoimmunity in both human and mouse, understanding the functional capacity of these cells as well as the mechanisms by which they develop may thus be useful in developing new therapeutics.

Each class of ILCs can be further subdivided into several subsets, which are discriminated based on tissue of residency, expression of cell-surface markers, and differential expression of signature cytokines. However, the extent to which ILC subsets and classes have unique and overlapping effector functions remained unclear. Furthermore, the functional distinctions between ILCs and their adaptive T cell counterparts were unknown. Finally, the developmental requirements for common gamma (γc) chain cytokines among ILC subsets and classes remained incompletely understood.

Using whole genome microarray, we have comprehensively analyzed the transcriptional profiles of mouse and human ILCs. For mouse ILCs, we compared ILC subsets and classes and generated subset-defining and class-defining transcriptional profiles. For human, we directly transcriptionally profiled tonsillar intraepithelial ILC1 (iILC1) and ILC3, and also compared these cells to their respective adaptive counterparts, Th1 and Th17, from the same microenvironment. Collectively, these data provide the first comprehensive transcriptional analyses of both mouse and human ILCs.

We identified a spontaneous loss-of-function mutation in the common gamma (γc) chain-signaling protein tyrosine kinase Jak3, causing a profound developmental block in ILC development. We investigated the requirements for γc cytokines in mouse ILC development through systematic analysis of Il7ra–/–, Il15–/–, and Il7ra–/–Il15–/– mice. We also tested the role of the immunosuppressive JAK inhibitor tofacitinib on human tonsillar ILC function. These data generate a more nuanced understanding of the role of γc cytokines in ILC development and function.

Language

English (en)

Chair and Committee

Marco Colonna

Committee Members

Maxim N. Artyomov, Takeshi Egawa, Gwendalyn J. Randolph, Wayne M. Yokoyama,

Comments

Permanent URL: https://doi.org/10.7936/K7416WJ1

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