The Treg profile in this study was similar to previous find- ings (14, 64). The cause of heightened levels of Tregs in CFS/ME is unknown.
Surface expression of CD73 on CD4+ T cells was correlated with an increase in Tregs in the CFS/ ME patients. CD73 is an ectonucleotidase required for aden- osine production (65).
At optimal conditions, CD4+ T cells, in particular Tregs produce low levels of adenosine deami- nases (ADA), which breaks down adenosine (66).
High lev- els of CD73 with limited amounts of ADA enhance the levels of extracellular adenosine in circulation and this may accu- mulate in immune cells altering their functions (67).
On the cell surface of many leucocytes including Tregs, ADA binds to CD26 eliminating anti-inflammatory adenosine (66) and reducing suppression by Tregs.
Reduced levels of CD26 have been reported on lymphocytes in CFS/ME patients and this in conjunction with an increase in CD73 may increase Treg suppression in CFS/ME (68). Tregs may suppress NK cytotoxic activity and T helper cells via a number of path- ways including the generation of adenosine by CD39 and CD73 molecules (69, 70).
In the presence of adenosine, NK cells also produce high levels of IFN-γ (71). Extracellular adenosine has anti-inflammatory effects on both innate and adaptive immunes, specifically, it may dampen the activa- tion of Th1 and Th17 cells (72, 73).
Adenosine may also inhibit CD8+ T cell cytotoxic activity and the release of pro- inflammatory cytokines by CD4+ T cell subsets (74–76).
In mice, the presence of adenosine receptor agonist reduces NK cytotoxic activity due to a decrease in cyclic adenosine monophosphate (77).
In T cells, CD73 dampens the release of pro-inflammatory cytokines by inhibiting NFκB activation (78), promoting a Th2 type response.
High levels of adeno- sine or ATP activates a negative feedback process that inhibits neutrophil function and protects against prolonged inflammation or injury (79, 80).
In summary, the findings from this study confirm a sub- stantial breakdown in immune tolerance and inflammatory mechanisms in patients with CFS/ME. This likely involves significant impairments in the NK-cell function, over-reactive Tregs, impaired DCs, neutrophils, dysregulation in cytokine levels and abnormal production of adenosine.
Collectively, these defects are overwhelming and further confirmatory studies may be required owing to the multifactorial and het- erogeneous nature of the disorder. Importantly, it may be nec- essary to confirm the levels of circulating type I interferons in CFS/ME patients and the exact profile of memory B cells and immature B cells that are disproportional in CFS/ME.