Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis

Abstract

Adenosine is an important regulator of the immune response and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies have shown that adenosine receptor (AR) agonists can be either anti- or pro-inflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1–20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8–14 days post-immunization, shortly before EAU expression, but ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses and this effect was γδ T cell-dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help improve the design of ADA- and AR-targeted therapies.

Ability of γδ T cells to modulate the Foxp3 T cell response is dependent on adenosine

“…Meanwhile, supernatants collected from activated and non-activated γδ T cells had a similarly enhancing effect ( Fig 4C ). We also tested the effect of γδ T cell supernatants after incubation with an adenosine-degrading enzyme ADA ( Fig 4D ) [ 31 – 33 ]. Interestingly, after ADA treatment the γδ T cell supernatant lost its enhancing effect ( Fig 4D , right panel).…”

Blockade of Extracellular ATP Effect by Oxidized ATP Effectively Mitigated Induced Mouse Experimental Autoimmune Uveitis (EAU)

“…Our studies on the effect of extracellular adenosine on autoimmune responses [ 31 – 35 ] have shown that such molecules have a strong effect on this autoimmune response [ 31 , 33 – 36 ]. Given that adenosine is a metabolite of ATP and that dysfunction of P2X7R signaling impaired T-cell function and suppressed T-cell activation [ 5 , 17 , 37 ], we wished to determine the effect of extracellular ATP signaling on autoimmune uveitis and the effect of blocking ATP binding on Th1 and Th17 autoimmune responses.…”

High level expression of A2ARs is required for the enhancing function, but not for the inhibiting function, of γδ T cells in the autoimmune responses of EAU

“…Our previous studies have established reliable assays for testing the effect of γδ T cells on autoimmune responses, in vitro and in vivo [ 3 , 4 , 32 – 35 ]. Testing of the adenosine effect used responder αβ T cells prepared from immunized TCR-δ -/- mice because the αβ T cell response to adenosine is strongly affected by <1% of γδ T cells [ 3 , 4 , 32 – 35 ]. T cell responses to the immunizing antigen were determined in the absence or presence of γδ T cells [ 3 , 4 , 32 – 35 ].…”

“…Testing of the adenosine effect used responder αβ T cells prepared from immunized TCR-δ -/- mice because the αβ T cell response to adenosine is strongly affected by <1% of γδ T cells [ 3 , 4 , 32 – 35 ]. T cell responses to the immunizing antigen were determined in the absence or presence of γδ T cells [ 3 , 4 , 32 – 35 ]. As expected, the addition of activated γδ T cells, but not of non-activated, γδ T cells, significantly enhanced the Th17 but did not enhance the Th1 response [ 5 , 7 , 8 ].…”

“…Since most previous studies examined the adenosine effect on Th1-type immune responses, we sought to determine whether Th17-type immune responses are similarly affected. To our surprise, adenosine had many different effects on αβ and γδ T cells [ 5 , 9 , 35 ], and it differs greatly with respect to its activation of Th1 and Th17 autoimmune responses. Moreover, unlike its suppressive effect on αβ T cells and DCs [ 27 , 48 , 55 ], adenosine enhanced the γδ T cell response and Th17 autoreactive T cell responses [ 9 ].…”