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.
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.
|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|
|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|
|Bimczok, Diane; Smythies, Lesley E; Waites, Ken B et al. (2013) Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. J Immunol 190:6626-34|
|Warren, Cirle Alcantara; Calabrese, Gina M; Li, Yuesheng et al. (2012) Effects of adenosine AÃ½Ã½Ã½A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice. BMC Infect Dis 12:13|
|Drygiannakis, Ioannis; Ernst, Peter B; Lowe, David et al. (2011) Immunological alterations mediated by adenosine during host-microbial interactions. Immunol Res 50:69-77|
|Wilson, Jeffrey M; Kurtz, Courtney C; Black, Steven G et al. (2011) The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6. J Immunol 186:6746-52|
|Ernst, Peter B; Wiznerowicz, Elizabeth B; Feldman, Sandford H et al. (2011) Pathogenesis of gastritis in ileitis-prone SAMP1/Yit mice. Keio J Med 60:65-8|
|Ernst, Peter B; Garrison, James C; Thompson, Linda F (2010) Much ado about adenosine: adenosine synthesis and function in regulatory T cell biology. J Immunol 185:1993-8|