Cytokines constitute a vast and complex network of molecules involved in almost every aspect of the immune system. Among these, IL-7 has emerged as a major T cell trophic cytokine affecting survival and homeostasis of T cells, processes that are highly disturbed in lupus-associated systemic autoimmunity. Consequently, we have made a concerted effort to define the role of IL-7 in the pathogenesis of this disease in mouse models. Our published and preliminary findings showed that blockade of IL-7R signaling effectively reduces disease severity in both murine lupus and EAE. Brief application of this treatment preferentially eliminated autoreactive T cells undergoing activation and, strikingly, additional studies showed that IL-7 provides a third signal beyond TCR and constimulatory receptor engagement to enhance activation and proliferation of low-affinity autoreactive T cells. Moreover, lymphadenopathy in murine lupus was associated with expansion of IL-7-producing lymphoid stromal cells, specifically fibroblastic reticular cells (FRCs). Accordingly, in this proposal, Specific Aim 1 will address the biochemical basis for IL-7-mediated enhancement of T cell activation, proliferation, survival, and metabolic status, while Specific Aim 2 will investigae the location and frequency of cellular sources of IL-7 in secondary lymphoid organs, the influence of inflammation-promoting TLRs and type I IFNs on IL-7 production and transcriptional status of these cells, and disease-modifying effects of genetic modifications that ablate IL-7 production by stromal and lymphatic endothelial cells (LECs). These biologic and mechanistic studies on IL-7 and its cellular producers will reveal novel aspects of autoimmune disease pathogenesis and may identify new therapeutic targets for intervention.

Public Health Relevance

A large family of soluble molecules, defined as cytokines, mediates both normal and abnormal immune responses. Among them, IL-7 plays a significant role in the survival of T cells, but when hyperproduced, it might contribute to autoimmune disease pathology, including lupus. Further understanding of the biology of this cytokine and its essential role in driving proliferation of autoreactive T cells could lead to the development of novel treatments for this and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR065919-01A1
Application #
8719533
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2014-07-11
Project End
2019-06-30
Budget Start
2014-07-11
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$416,900
Indirect Cost
$196,900
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037