Adipose Tissue T Cell Function and Diversity in Obese Mice and Humans
dc.contributor.author | Porsche, Cara | |
dc.date.accessioned | 2020-10-04T23:23:54Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2020-10-04T23:23:54Z | |
dc.date.issued | 2020 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/162946 | |
dc.description.abstract | Adipose tissue induced chronic low-grade inflammation is a critical link between obesity and insulin resistance. Despite studies implicating adipose tissue T cells (ATT) in the initiation and persistence of adipose tissue inflammation, fundamental gaps in knowledge regarding ATT function impedes progress towards understanding their role in type II diabetes. This dissertation explores the mechanisms of ATT maintenance via interactions with antigen presenting cells (APC), the tissue specific characteristics of ATTs, and how obesity regulates ATT inflammatory function upon activation. We find that the network between ATTs and peptide-majorhistocompatability complex II (pMHCII) presented on the cell surface of adipose tissue dendritic cells (ATDC) is required for ATT maintenance. Knocking down MHCII on dendritic cells with CD11cCre x MHCIIfl/fl (M11cKO) mice reconfigures ATT composition, but does not significantly impact systemic glucose or insulin sensitivity. To address gaps in the understanding of how obesity alters ATT function, we employed an in-vitro activation assay to analyze T cell activation in visceral adipose. Our findings challenge the dogma that ATTs acquire pro-inflammatory potential in obese fat, and show that measures of ATT activation based on cellular markers, proliferation, and cytokine secretion are impaired in obese mice and humans. Chronic antigen presentation or soluble mediators from obese stromal vascular cells are sufficient for driving ATT impairment. Single cell RNA sequencing of mouse CD3+ ATTs shows diversity in T cell subsets and gene expression dependent upon adipose tissue depot of origin and obesity. There are nine distinct subsets of ATTs and 12 weeks of high fat diet (HFD) feeding influences their proportions. In visceral adipose tissue depots where functional ATT impairment was observed, we see HFD induces genes enriched in models of T cell exhaustion. Further studies are required to pinpoint the specific mechanisms leading to ATT exhaustion and to determine whether ATT inflammatory impairment influences insulin resistance in the context of obesity. | |
dc.language.iso | en_US | |
dc.subject | Obesity | |
dc.subject | Inflammation | |
dc.subject | Adipose tissue | |
dc.subject | Antigen presenting cells | |
dc.subject | T cells | |
dc.title | Adipose Tissue T Cell Function and Diversity in Obese Mice and Humans | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Immunology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Lumeng, Carey Nien-Kai | |
dc.contributor.committeemember | Carty, Shannon | |
dc.contributor.committeemember | Chang, Cheong-Hee | |
dc.contributor.committeemember | Lukacs, Nicholas W | |
dc.contributor.committeemember | Qi, Ling | |
dc.subject.hlbsecondlevel | Microbiology and Immunology | |
dc.subject.hlbsecondlevel | Physiology | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.subject.hlbtoplevel | Science | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/162946/1/porsche_1.pdf | en_US |
dc.identifier.orcid | 0000-0003-1581-5571 | |
dc.identifier.name-orcid | Porsche, Cara; 0000-0003-1581-5571 | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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