MARINELARENA-DISSERTATION-2020.pdf (13.27 MB)

Identification of a Novel OX40L+ Dendritic Cell Subset That Selectively Expands Regulatory T-Cells

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posted on 01.05.2020, 00:00 by Alejandra Marinelarena
Granulocyte macrophage-colony stimulating factor (GM-CSF) has been demonstrated to play a protective role in autoimmune disease through the dendritic cell-mediated expansion of regulatory T-cells (Tregs). We have previously shown that GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce expansion of Tregs through the surface-bound molecule OX40L; however, the physiological relevance of this ex vivo derived DC subset remained to be elucidated. We determined OX40L+G-BMDCs, and not OX40L-G-BMDCs, were responsible for the selective expansion of Tregs expressing functionally suppressive markers. Phenotypic characterization of OX40L+G-BMDCs revealed higher expression levels of co-stimulatory/co-inhibitory molecules, CD80, CD86, and PDL2. Furthermore, OX40L+CD11c+ cells, phenotypically and functionally similar to OX40L+G-BMDCs, were identified in the spleen, brachial lymph nodes and liver of GM-CSF treated mice, but absent in the thymus. Concordantly, the percentage of functionally suppressive Tregs was increased in the spleen, brachial lymph nodes, and liver, of GM-CSF treated mice, but not the thymus, implying a role for OX40L+ DCs in peripheral Treg expansion. Microarray analysis of OX40L+G-BMDCs and OX40L-G-BMDCs revealed significant differences in the expression of PDL2, IL33, CCL17, and CCL22 molecules which could play important roles in the tolerogenic function of OX40L+CD11c+ DCs. Comparing the transcriptome data from OX40L+ G-BMDCs to that of all immune cell types from the ImmGen database revealed OX40L+ G-BMDCs to be distinct from steady-state immune cells. These findings suggest that OX40L+CD11c+ DCs represent a unique tolerogenic DC subset which may play an essential role in maintaining Treg homeostasis and suppressing autoimmunity.

History

Advisor

Prabhakar, Bellur

Chair

Prabhakar, Bellur

Department

Microbiology and Immunology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Freitag, Nancy McLachlan, Alan He, Bin Shukla, Deepak Federle, Michael Layden, Brian

Submitted date

May 2020

Thesis type

application/pdf

Language

en

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