T lymphocytes that recognize self or innocuous antigens are subject to regulation by peripheral mechanisms of tolerance, the loss of which results in autoimmune and inflammatory diseases. Recent studies have revealed the cytokine transforming growth factor-? (TGF-?) as one of the most crucial and pleiotropic regulators of T cell differentiation and function; yet how TGF-? controls T cell tolerance remains incompletely understood. Following our surprising observation that ablation of TGF-? receptor in T cells, but not regulatory T (Treg) cell deficiency, results in rampant autoimmune disease in a murine model of diabetes, we have found that TGF-? signaling in T cells is specifically required for suppressing inflammatory monocyte responses in target tissues. In addition, TGF-? receptor-deficient autoreactive T cells, but not autoreactive T cells from Treg cell-deficient mice, produce copious amounts of the monocyte activation cytokine GM-CSF. Based on these observations, we hypothesize that TGF-? promotes T cell tolerance primarily via Treg cell-independent mechanisms in part by inhibiting GM-CSF expression and the consequent monocyte responses; and monocytes foster the development of immunopathology by sustaining autoimmune T cell responses as well as directly inducing tissue damage. To address this new concept of adaptive-innate immune crosstalk in TGF-? control of peripheral T cell tolerance, we will first determine the precise mechanisms by which T cell TGF-? signaling inhibits monocyte responses. Using genetic and pharmacological approaches, we will investigate whether GM-CSF expressed by TGF-? receptor-deficient T cells is essential for mobilizing inflammatory monocytes, and whether GM-CSF can be targeted for disease therapy in models of autoimmune diabetes and inflammatory bowel disease (IBD). Using genomic and biochemical approaches, we will further explore the function of Smad proteins in TGF-? control of GM-CSF expression in T cells. Secondly, we will determine how monocytes modulate the immunopathology triggered by TGF-? receptor-deficient T cells. We will use monocyte-deficient mouse models to investigate the definitive role of monocytes in diabetes and IBD. In addition, we will use a monocyte transfer system to explore the functions of monocyte-expressed MHC Class II as well as iNOS and TNF-? in control of T cell responses and tissue damage, respectively. Successful completion of the projects outlined in this proposal will not only generate mechanistic insights into the crosstalk between adaptive and innate responses in the development of immunopathology, but also provide novel immunotherapy strategies for autoimmune and inflammatory diseases.

Public Health Relevance

T lymphocytes play a key role in autoimmune and inflammatory diseases that collectively affect approximately 50 million Americans. It has been shown that the regulatory cytokine TGF-? has a pivotal function in promoting T cell tolerance in humans as well as in animal models of autoimmune and inflammatory diseases. Experiments proposed in this project will define the in-depth mechanisms by which TGF-? regulates T cell tolerance in peripheral tissues, which will ultimately enhance our ability to manipulate the T cell triggered immunopathology in human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI122264-07
Application #
9210596
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Bourcier, Katarzyna
Project Start
2016-02-01
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
7
Fiscal Year
2017
Total Cost
$524,247
Indirect Cost
$218,385
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
Research Institutes
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065