Background: The CD39/CD73/adenosine (ADO) pathway was associated with immunosuppression in multiple diseases; yet, its precise role in mediating immune activation and inflammation (IA/INFL) during HIV-1/SIV infection remains unclear.
Methodology: We compared and contrasted the expression of markers related to either ADO production (CD39 and CD73) or ADO breakdown (CD26) on both regulatory (Tregs) and conventional T cells isolated from blood, lymph nodes (LNs), and intestine of nonprogressive (African green monkeys-AGMs) and progressive (pigtailed macaques-PTMs) models of SIVagm infection. Expression of ADO-related markers was assessed by flow cytometry during acute, early and late chronic infection, compared to preinfection levels and correlated with T cell immune activation (CD38/HLA-DR and Ki-67), monocyte activation (sCD14 and sCD163), and inflammation (CRP and proinflammatory cytokines).
Results: Baseline expression levels of both CD39 and CD73 on CD8+ Tregs isolated from blood and in CD4+ Tregs isolated from LNs and intestine were intrinsically high in AGMs. However, CD39, CD73 and CD26 expression remained at baseline levels throughout SIVagm infection in all the cells from different compartments of the AGMs, which control chronic IA/INFL. Conversely, in PTMs, which exhibit increasing IA/INFL markers with disease progression, CD39 expression on circulating conventional T cells and Tregs significantly increased during the late stages of SIV infection. In the LNs, expression of both CD39 and CD73 was significantly increased on conventional T cells and Tregs, while only CD73 significantly increased after infection on Tregs in the intestine. In the LNs, a dramatic increase of CD26 expression on CD39 and CD73 cells occurred only during acute infection, while being maintained throughout infection in the intestine. Increased CD39 and CD73 expression in SIV-infected PTMs did not positively correlate with control of IA/INFL.
Conclusions: CD39/CD73 expression on Tregs and T conventional cells undergo different dynamics among different lymphoid compartments and among different NHP species. Despite a higher baseline adenosine production in the AGM nonprogressive model, lack of variation of CD39/CD73 and CD26 markers suggest that ADO pathway is not critical for the control of IA/INFL in AGMs. Conversely in the progressive SIV infection of PTMs, significant changes in CD39/CD73 and CD26 expression occur in tissues rather than blood, suggesting that future studies of the ADO pathway should focus on the tissue sites of viral replication. In pathogenic infections, increased CD39/CD73 expression and subsequent ADO production may be counteracted by the early increases in the expression of CD26, which is associated with adenosine deaminase.