Abstract
CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness.
Highlights
Type 1 Cytotoxic CD8+ T (Tc1) cells are pivotal in the elimination of infected and transformed cells
To understand the role of CD73 ectonucleotidase and adenosine during CD8+ effector cell differentiation, we first evaluated the kinetics of expression of CD73 and CD39 on in vitro-activated CD8+ T lymphocytes
When the cells were preincubated with AMP, activated T cells produced higher levels of adenosine that naïve T cells and this was reversed by the addition of the CD73 enzymatic activity inhibitor APCP (Figure 1E)
Summary
Type 1 Cytotoxic CD8+ T (Tc1) cells are pivotal in the elimination of infected and transformed cells. The differentiation process that culminates in the generation of effector T CD8+ lymphocytes is not homogeneous, and during the immune response, there are T cell subsets with varying proliferative and cytotoxic capacities (Williams and Bevan, 2007; Gattinoni et al, 2012). Two populations can be CD73 Restrains Tc1 Responses distinguished following CD8+ T cell activation and clonal expansion: short-lived effector cells and memory effector cells (Kaech et al, 2003; Badovinac et al, 2004; Joshi et al, 2007). Short-lived CD8+ effector cells are characterized by a more significant commitment to the effector profile and a lower survival and self-renewal capacity than memory effector cells. TCM cells are characterized by a lower commitment to effector differentiation and the expression of receptors for migration to secondary lymphoid organs, such as CD62L and CCR7. During T cell effector differentiation, the cells gradually upregulate transcription factors related to effector differentiation, such as T-bet, Blimp, and reduce transcription factors related to a less differentiated state such as TCF-7, Lef-1, Bcl-6, among others (Zhang and Bevan, 2011; Kaech and Cui, 2012)
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