THE ABSENCE OF C3AR AND C5AR SIGNAL TRANSDUCTION PROMOTES T REGULATORY CELL DIFFERENTIATION AND REGULATES IMMUNOLOGIC TOLERANCE

Here, we demonstrate that when C3aR and C5aR signals are not transduced into CD4+ T cells, PI-3K¿-AKT-mTOR signaling ceases, PKA activation increases, auto-inductive TGF-ß1 signaling initiates, and CD4+ T cells become Foxp3+ T regulatory cells (iTregs). Endogenous TGF-ß1 suppresses C3aR and C5aR signaling by preventing C3a and C5a production and upregulating C5L2, an alternate C5a receptor. Absent C3aR and C5aR signaling decreases costimulatory molecule and IL-6 production and augments IL-10 production. The resulting iTregs exert robust suppression, possess enhanced stability, and suppress ongoing autoimmune disease. It has been difficult to generate stable human Tregs with potent suppressor activity in vitro with TGF-ß1. We used the insights from this work to generate human iTregs with potent suppressor activity by antagonizing C3aR and C5aR signal transduction during induction.To maintain tolerogenic responses against benign foreign and self antigens, they must be processed and their peptides presented in lymph nodes (LNs) to cognate T cells by immature dendritic cells (DCs). Here we show that maintenance of DCs and CD4+ T cells in an immature state by decay accelerating factor (DAF or CD55) is essential for peripheral Foxp3+ T regulatory cell (iTreg) induction. In the absence of its restraint of C3a/C5a receptor (C3aR/C5aR) signaling, DCs in the anterior chamber (a.c.) of the eye and in Peyer’s patch of the gut express costimulatory B7-1,2/CD40 rather than co-inhibitory ICOS-L/PD-L1 and, following their transit to their LNs, evoke a T effector instead of a tolerogenic response. Consistent with this, a.c. pre-injection or oral pre-feeding of ovalbumin (ova) in WT mice and in WT chimeras possessing Daf1–/–C3aR–/–C5aR–/– bone marrow (BM) but not Daf1–/– BM increased ocular TGF-ß1 production, induced iTregs, and suppressed subsequent ova-specific DTH, CD4+, CD8+, and IgG2ab responses. Moreover, DCs from Daf1+/+C3aR–/–C5aR–/– mice expressed higher co-inhibitory ICOS-L/PD-L1 than DCs from WT mice and produced markedly more iTregs.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Pathology

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Strainic, Michael George, Jr

Contributors dc:contributor

• Anderson, James
• Medof, M Edward

• Immunology
• C3aR
• C5aR
• DAF
• CD55
• T cell activation
• T cell
• T regulatory cell
• Treg
• T cell suppression
• Treg induction
• complement
• complement mediated T cell activation
• G-protein coupled receptor
• Foxp3

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1363707372

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1363707372