Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A1, A2a, A2b, A3) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A2 receptor agonists and was blocked by selective A2a and A2b receptor antagonists, indicating that adenosine was mediating its effect through A2 receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A2 receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.
The identification of genes associated with colonization and persistence of Helicobacter pylori in the gastric mucosa has been limited by the lack of robust animal models that support infection by strains whose genomes have been completely sequenced. Here we report that an interleukin-12 (IL-12)-deficient mouse (IL-12 ؊/؊ p40 subunit knockout in C57BL/6 mouse) is permissive for infection by a motile variant (KE88-3887) of The Institute For Genomic Research-sequenced strain (KE26695) of H. pylori. The IL-12-deficient mouse was also more permissive for colonization by the mouse-colonizing Sydney 1 strain of H. pylori than were wild-type C57BL/6 mice. Differences in colonization efficiency were demonstrated by mouse challenge with SS1 strains containing loss-of-function mutations in two genes (hspR and hrcA), whose products negatively regulate several heat shock genes. Helicobacter pylori colonizes the gastric mucosa of humans, producing a chronic gastritis that may remain asymptomatic for many years. In about 10% of individuals, more severe disease manifestations will occur such as duodenal and gastric ulcers, atrophic gastritis, and intestinal metaplasia, all risk factors for gastric cancer (20,40,42). The remarkable ability of H. pylori to establish lifelong infections is not well understood but likely involves evasion or modulation of host immune responses as well as adaptation (through mutation and selection) to the unique physiology of each individual host (3). In addition, different disease pathologies seem to correlate with particular H. pylori genotypes, with strains containing the cagassociated pathogenicity island and cagA gene (cytotoxinassociated gene) and vacA (vacuolating cytotoxin) correlating with more severe disease (11,14,39). There is much genetic diversity in these genes and in others such as the restriction modification genes (9) among strains from different geographic regions and people of different ethnicities (1, 10, 13). The evaluation of genetic diversity among strains and identification of genes associated with severity of infection have generally been hampered by the lack of good animal models (9,25,36).Robust animal models of infection are also a necessary component in the discovery process for new therapeutics or the evaluation of vaccine candidates (12,23,47). While several animal models have been developed, these models are limited to a few animal-adapted strains (9,22,36) or support only transient infection (25). Mouse-adapted strains such as the Sydney 1 strain (SS1), Hp1, and a few others are difficult to manipulate genetically (37) and usually require high infectious doses in order to establish infection (36). In such mouse models requiring high colonization thresholds, many genes scored as necessary for colonization may be dispensable in a more permissive animal. Another limitation of existing mouse-colonizing strains is that systematic whole-genome approaches to the study of virulence determinants cannot be performed, as the genomes of mouse-colonizing strains have not been se...
Adenosine is an immunosuppressive molecule that is associated with the microenvironment of solid tumors. Mouse T cells activated with anti-CD3 antibody in the presence of adenosine with or without coformycin (to prevent adenosine breakdown by adenosine deaminase) exhibited decreased tyrosine phosphorylation of some intracellular proteins and were inhibited in their ability to proliferate and synthesize interleukin (IL)-2. In addition, adenosine interfered with activation-induced expression of the co-stimulatory molecules CD2 and CD28. Activation-induced CD2 and CD28 expression was also diminished when T cells were activated in the presence of anti-IL-2 and anti-CD25 antibodies to neutralize IL-2 bioactivity. Collectively, these data suggest that CD2 and CD28 up-regulation following T cell activation is IL-2-dependent; and that adenosine inhibits activation-induced T cell expression of CD2 and CD28 by interfering with IL-2-dependent signaling. The inhibitory effect of adenosine on activation-induced CD2 and CD28 expression could not be attributed to cyclic AMP (cAMP) accumulation resulting from the stimulation of adenylyl cyclase-coupled adenosine receptors, even though cAMP at concentrations much higher than those generated following adenosine stimulation was inhibitory for both CD2 and CD28 expression. We conclude that adenosine interferes with IL-2-dependent T cell expression of co-stimulatory molecules via a mechanism that does not involve the accumulation of intracellular cAMP.
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