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Mechanism of expansion of T-regulatory cells by GM-CSF induced bone marrow derived dendritic cells

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Title: Mechanism of expansion of T-regulatory cells by GM-CSF induced bone marrow derived dendritic cells
Author(s): Gopisetty, Anupama
Advisor(s): Prabahakar, Bellur S.
Contributor(s): Chenthamarakshan, Vasu; Shukla, Deepak; Freitag, Nancy; Fantuzzi, Giamila
Department / Program: Microbiology and Immunology
Graduate Major: Microbiology and Immunology
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): Dendritic cells GM-CSF T-regulatory cells Notch signalling Granulocyte-macrophage colony stimulating factor
Abstract: Experimental autoimmune thyroiditis (EAT) is a T-cell mediated autoimmune disease which is characterized by the thyroid infiltration of autoreactive CD4+T-cells that eventually leads to destruction of the thyroid gland and results in hypothyroidism. Our earlier work demonstrated that administration of granulocyte macrophage colony stimulating factor (GM-CSF) can protect the animals from ongoing EAT and restore normal thyroid function. GM-CSF treated animals had increased numbers of CD8a- dendritic cells (DCs) and FoXP3+ T-regulatory cells (T-regs). In order to understand the mechanism by which GM-CSF imparts this tolerogenic effect upon DCs, we have simultaneously studied the effects of GM-CSF upon mature splenic DCs as well as bone marrow (BM) precursors. Our study indicates that GM-CSF primarily exerts its effects on BM precursors, which helped increase the number of Tregs by two distinct mechanisms: One was they expanded nTregs selectively in a contact and IL-2 dependent, but TCR independent manner; and the other is they induced Tregs in a contact independent, but TGF- and TCR signal dependent manner. Interestingly, the expansion is predominantly a consequence of proliferation of existing FOXP3+ T-regs in a contact dependent mechanism. Our efforts to understand the underlying mechanism revealed that signaling mediated by Jagged-1 and OX40 ligand expressed on BMDCs are required for the proliferation of FOXP3+ T-regs. These studies allowed us to conclude that signaling mediated by both notch 3 and OX40 are likely involved in the selective proliferation of FOXP3+ T regs and blocking either of the signaling could abrogate their expansion. Furthermore OX40L+Jagged1+ BMDCs were able to suppress ongoing autoimmune thyroiditis in mice.
Issue Date: 2012-12-07
Genre: thesis
Rights Information: Copyright 2011 Anupama Gopisetty
Date Available in INDIGO: 2012-12-07
Date Deposited: 2011-12

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