Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Regulatory T cells (Tregs) are indispensable in the human immune system in the maintenance of self-tolerance and immune homeostasis. The dysregulation of Treg number and/or function plays a critical role in the pathogenesis of cancer, allergy and human autoimmune pathologies such as multiple sclerosis, psoriasis, rheumatoid arthritis and diabetes. The primary aim of this research was to determine the molecular mechanisms and cellular interactions which promote human Treg induction. From umbilical cord blood (UCB) samples, we found that antigen receptor stimulation of UCB T cells via a CD14+ monocyte population leads to a predominant induction of Tregs.

Further studies identified a CD14+ cell subset with increased cell surface expression of CD36 and the TGF-beta related latency associated peptide, LAP. We termed this unique cellular subset CD14+CD36HI monocytes, and further demonstrated their expression of the LAP-TGF-beta binding transmembrane molecule GARP, functioning to tether TGF-beta to the cell surface. Additionally, we found that CD14+ CD36HI monocytes produce significantly higher levels of latent TGF-beta than other antigen presenting cell (APC) subsets. Notably, we demonstrated that CD14+ CD36HI monocytes are alone sufficient to induce human Foxp3+ Treg differentiation from naïve CD4+ T cells. Furthermore, we demonstrated that genetic knock-down of CD36 or GARP expression in an APC significantly decreases its ability to promote Treg induction, suggesting a critical role for CD36 and GARP expression in human Treg induction.

To our knowledge, these studies are both the first demonstration of GARP expression on a human cell subset other than activated Tregs and demonstration of a novel functional role for GARP in human Treg induction. Taken together, our data indicate that CD14+ CD36HI monocytes are sufficient to induce human Treg differentiation from naïve CD4+ T cells, and that this Treg induction is uniquely dependent on the TGF-beta activation and signaling pathway. The ability to induce human Treg differentiation makes CD14+ CD36HI monocytes and GARP mediated cell surface bound TGF-beta unique and novel therapeutic targets for the treatment of autoimmune conditions, transplant rejection, allergy and conditions of disrupted maternal-fetal tolerance.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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