A breakdown of immune tolerance and the generation of pro-inflammatory lymphocytes cause autoimmune diseases, including Multiple Sclerosis (MS). Dendritic cells (DCs) induce immunity and tolerance and therefore represent a promising target for new immune-therapies of MS. Pathways of T cell tolerance that include deletion, anergy, and immune-suppression of autoreactive T cells were shown to confer protection from disease in autoimmune Experimental Acute Encephalomyelitis (EAE), a mouse model of MS. However, the specific mechanisms of tolerance mediated by DCs remain unclear. We recently discovered that Homeodomain Only Protein (Hopx) directs Treg cell-mediated immune unresponsiveness induced by DCs. Hopx is a transcription co-factor that differently regulates expression of c- jun/c-fos and other genes through its interactions with other proteins including Serum Response Factor (SRF). Our most recent findings reveal that DCs mediate tolerance through intimately linked pathways involving the early induction of tolerance in T cells that become unresponsive to activation in EAE, induce expression of Hopx and Hopx+/Foxp3neg cells can convert into Hopx+/Foxp3+ peripheral (p)Treg cells. These extrathymically- induced pTreg cells then mediate long-lasting tolerance to block autoimmune EAE. Hopx expressed in pTreg cells maintains the functions of these regulatory cells by inhibiting their expression of IL-2. Our results firmly establish Hopx as the first characterized transcription co-factor specifically required for DC- induced tolerance to avert autoimmunity, and they open a new area of investigation in immune tolerance mediated by DCs. Our long-term goals are to establish a novel and comprehensive model of Hopx functions in tolerance. We will reveal molecular pathways of Hopx in pTreg cells by clarifying functions of specific Hopx molecular targets including IL-2 in Aim 1. We will discern regulation of Hopx expression in tolerance in Aim 2. We will define the role for Hopx in diverse mechanisms of tolerance mediated by various types of DCs in Aim 3. The results of the proposed experiments may become a foundation of more selective and efficient therapies for MS as well as other types of autoimmune diseases.

Public Health Relevance

A breakdown of immune tolerance and the generation of pro-inflammatory lymphocytes cause autoimmune diseases, including Multiple Sclerosis (MS). The goals of this project are to establish a novel and comprehensive model of Hopx functions in tolerance. The results of the proposed experiments may become a foundation of more selective and efficient therapies for MS as well as other types of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI113903-01
Application #
8767156
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2014-05-05
Project End
2019-04-30
Budget Start
2014-05-05
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$376,669
Indirect Cost
$126,669
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103