Immunological tolerance reflects complex interactions amongst multiple cells. In the digestive tract, Th cells limit the host response to dietary or microbial antigens including those that are introduced into the lumen during neonatal life. The importance of appropriate immune responses to enteric microbiota is illustrated in mouse models in which Helicobacter hepaticus induces regulatory Th cells (Treg) in normal mice while exacerbating intestinal inflammation in animals in which regulatory T cell function is perturbed. Studies suggest that chronic, relapsing inflammatory bowel diseases (IBD) in humans result from inappropriately regulated immune responses to enteric antigens in genetically susceptible hosts. However, few studies have examined the development of tolerance to luminal microbiota during the post-weaning period but the responses during this time may affect the risk of developing IBD later in life. The exact etiology and pathogenesis of IBD is unclear but there is substantial interest in the role of """"""""natural"""""""" or """"""""adaptive"""""""" Treg in intestinal immune regulation. One factor that mediates anti-inflammatory activity is adenosine. Adenosine accumulates in inflamed or hypoxic tissues largely due to CD39 mediating the dephosphorylation of ATP to ADP then to 5'-AMP while CD73 catalyzes the terminal reaction to convert 5'AMP to adenosine. Activation of A2A adenosine receptors (A2AAR) on Th cells produces a series of responses that have been categorized as anti-inflammatory. Our lab discovered that the expression of the A2AAR by Th cells is required for optimal Treg function. Subsequently, Treg have been reported to express CD39 and CD73 and enhance Treg function by synthesizing adenosine. We propose the general hypothesis that Treg express the enzymes required for adenosine synthesis and this mediator contributes to the control of inflammation. Specifically, we hypothesize that the development of tolerance during the post-weaning period is favored by adenosine derived from Treg. The objective of this proposal is to assess how adenosine contributes to the ability of Treg to confer tolerance to the intestinal microbiota throughout the post-weaning period.
The specific aims are:
Aim 1. Characterize the role of adenosine in Th cell development during the post-weaning period.
Aim 2. Determine the ability of Th cell subsets to synthesize and respond to adenosine.
Aim 3. Characterize the mechanisms by which adenosine modulates Th cell responses. Together, these studies will use novel animal models and pharmacological reagents to investigate an innovative and complementary model for the control of effector Th cell function. With this new information, adenosine receptor agonists may be exploited pharmacologically for the treatment of chronic inflammatory diseases such as IBD.

Public Health Relevance

This proposal will examine the physiological role by which adenosine receptors impact the development of immune tolerance that inhibits pathogenic T cell responses to bacteria found in the intestinal lumen. Establishing a novel role for adenosine and its receptors in this process is not only a completely new direction for understanding the biology of Treg, but it will lead to future translational studies in humans that model the induction of long-term antigen-specific immune tolerance. This new information may have therapeutic applications for the prevention or treatment of inflammatory bowel diseases and possibly other illnesses that can be controlled by regulatory T cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Garcia-Carbonell, Ricard; Wong, Jerry; Kim, Ju Youn et al. (2018) Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. Proc Natl Acad Sci U S A 115:E9192-E9200
Tyler, Christopher J; PĂ©rez-Jeldres, Tamara; Ehinger, Erik et al. (2018) Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease. Inflamm Bowel Dis 24:2366-2376
Ernst, Peter B; Carvunis, Anne-Ruxandra (2018) Of mice, men and immunity: a case for evolutionary systems biology. Nat Immunol 19:421-425
Kurashima, Yosuke; Yamamoto, Daiki; Nelson, Sean et al. (2017) Mucosal Mesenchymal Cells: Secondary Barrier and Peripheral Educator for the Gut Immune System. Front Immunol 8:1787
Chu, Hiutung; Khosravi, Arya; Kusumawardhani, Indah P et al. (2016) Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science 352:1116-20
Das, Soumita; Sarkar, Arup; Choudhury, Sarmistha Sinha et al. (2015) ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome. Cell Mol Gastroenterol Hepatol 1:311-324
Kurtz, Courtney C; Drygiannakis, Ioannis; Naganuma, Makoto et al. (2014) Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells. Am J Physiol Gastrointest Liver Physiol 307:G338-46
Chang, John T; Sandborn, William J; Ernst, Peter B (2014) Studies in human intestinal tissues: is it time to reemphasize research in human immunology? Gastroenterology 147:26-30
Das, Soumita; Sarkar, Arup; Ryan, Kieran A et al. (2014) Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells. FASEB J 28:2214-24
Boland, B S; Boyle, D L; Sandborn, W J et al. (2014) Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis. Aliment Pharmacol Ther 40:477-85

Showing the most recent 10 out of 20 publications