Decreased CD73+ Double-Negative T Cells and Elevated Level of Soluble CD73 Correlated With and Predicted Poor Immune Reconstitution in HIV-Infected Patients After Antiretroviral Therapy

Abstract

Although extensive use of antiretroviral therapy (ART) has made great progress in controlling HIV replication and improving CD4+ T cell recovery, the immune reconstitution remained insufficient in some patients, who were defined as poor immunological responders (PIRs). These PIRs were at a high risk of AIDS-related and non-AIDS complications, resulting in higher morbidity and mortality rate. Thus, it is a major challenge and urgently needed to distinguish PIRs early and improve their immune function in time. Immune activation is a key factor that leads to impaired immune reconstitution in people living with HIV (PLWH) who are receiving effective ART. Double negative T cells (DNT) were reported to associate with the control of immune activation during HIV infection. However, the precise mechanisms by which DNT cells exerted their suppressive capacity during HIV infection remained puzzled. CD73, both a soluble and a membrane-bound form, display immunosuppressive effects through producing adenosine (ADO). Thus, whether DNT cells expressed CD73 and mediated immune suppression through CD73-ADO pathway needs to be investigated. Here, we found a significant downregulation of CD73 expression on DNT cells in treatment-naïve PLWH (TNs) compared to healthy controls, accompanied with increased concentration of sCD73 in plasma. Both the frequency of CD73+ DNT cells and the level of plasma sCD73 recovered after ART treatment. However, PIRs showed decreased percentage of CD73+ DNT cells compared to immunological responders (IRs). The frequency of CD73+ DNT cells was positively correlated with CD4+ T cell count and CD4/CD8 ratio, and negatively correlated with immune activation in PLWH. The level of sCD73 also showed a negative correlation to CD4+ T cell count and CD4/CD8 ratio. More importantly, in the present cohort, a higher level of sCD73 at the time of initiating ART could predict poor immune reconstitution in PLWH after long-term ART. Our findings highlighted the importance of CD73+ DNT cells and sCD73 in the disease progression and immune reconstitution of PLWH, and provided evidences for sCD73 as a potential biomarker of predicting immune recovery.

Elevated Foxp3+ double-negative T cells are associated with disease progression during HIV infection

“…In line with previous studies, we also found that DNT cells increased with disease progression of HIV infection ( Figure S1A ) ( 24 ). To further investigate the potential role of Foxp3 in DNT cells during HIV infection, we performed intracellular flow cytometric analysis of Foxp3 in DNT cells.…”

“…CD25 rendered Treg cells able to rapidly sense IL-2 produced by self-reactive conventional T cells early in the immune response and compete for growth factors ( 27 ). CD39 was an ectoenzyme that converted ATP into adenosine in tandem with CD73, which was reported to involve in the immune regulation mediated by DNT cells in our recent study ( 24 ). Additionally, GITR triggering in vivo effectively increased the absolute number of cells through enhanced proliferation ( 36 ), which was in line with high levels of Ki-67 in Foxp3 + DNT cells.…”

“…Previous studies have demonstrated that DNT cells accumulated and played a regulatory role in the control of immune activation during HIV infection ( 20 , 22 , 24 ); however, the underlying mechanisms need to be thoroughly explored. In this study, we found a subpopulation of DNT cells which shared the key factor “Foxp3” of CD4 + Tregs enriched in PLWH with CD4 + T cell count less than 200 cells/µl.…”

“…These cells exert immunosuppressive effects via various mechanisms, including high-level expression of CTLA-4 to downregulate the costimulatory molecules CD80 and CD86 on antigen-presenting mature DCs ( 21 ), production of anti-inflammatory cytokines such as IL-10, TGF-β ( 22 ), and induction of apoptosis via Fas/FasL pathway ( 23 ). Recently, accumulating evidence figured out a potential role of DNT cells to provide immunosuppression during HIV/SIV infection ( 15 , 20 , 22 , 24 ), but the related mechanism needs to be further explored.…”

The Hypoxia-regulated Ectonucleotidase CD73 is a Host Determinant of HIV Latency

“…It is important to note that in recent years increasing circumstantial evidence has been gathered, independently suggesting a critical role for either hypoxia [53][54][55][56][57] , CD73 expression [60][61][62] or adenosine signaling [63][64][65][66][67] in HIV infections. Our data now implies a direct, causal connection that links the hypoxic regulation and adenosineproducing enzymatic activity of CD73 to the establishment and persistence of viral reservoirs.…”