The Multifaceted Actions of CD73 During Development and Suppressive Actions of Regulatory T Cells

Abstract

Adenosine (Ado) has been shown to have immunosuppressive effects in a variety of diseases. It can either be released directly into the extracellular environment by cells, or it can be produced by degradation of ATP within the extracellular spaces. This extracellular pathway is facilitated by the concerted actions of the ectoenzymes CD39 and CD73. In a first step CD39 dephosphorylates ATP to ADP and AMP, respectively, and in a second step CD73 converts AMP to Ado. Thus, activity of CD73 on the cell surface of cells is the rate limiting step in the generation of extracellular Ado. Among T cells, CD73 is most abundantly expressed by regulatory T cells (Tregs) and is even upregulated after their activation. Functionally, the generation of Ado by CD73+ Tregs has been shown to play a role in immune suppression of dendritic cells, monocytes and T cells, and the defined expression of CD73 by Tregs in immunosuppressive environments, such as tumors, made CD73 a novel checkpoint inhibitor. Therefore, therapeutical intervention by anti-CD73 antibodies or by chemical inhibitors of the enzymatic function is currently under investigation in some preclinical animal models. In the following we summarize the expression pattern and the possible functions of CD73 in T cells and Tregs, and exemplify novel ways to manipulate CD73 functions in Tregs to stimulate anti-tumor immunity.

Bispecific antibodies tethering innate receptors induce human tolerant-dendritic cells and regulatory T cells

“…A high molecular concentration of Bic seems unnecessary and even counterproductive, as we also observed for Bic05 and Treg differentiation ( Figure 3C ). For Bic05, induced Tregs were both IL-10 + and Foxp3 + and expressed more CD73 than zym-induced Tregs, which suggests the participation of purinergic signals ( 51 , 52 ). Finally, both Bics seemed able to confer regulatory properties to PBMC populations with the development of particular Tregs.…”

Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers

“…Previous studies have indicated that elevated levels of CD73 are often associated with an increase in immunosuppressive cell populations such as Tregs, MDSCs, and tumor-associated macrophages (TAMs) ( 32 , 33 ). To analyze the affect of OTUD4 in modulating tumor immunity, we examined the tumor immune infiltrates using a high-dimensional spectral flow cytometry (CyTEK) panel that incorporated hallmark markers for all major immune populations as described previously ( 34 ).…”

Probiotic Limosilactobacillus reuteri DSM 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia and Chronic Hepatitis in Mice

“…The primary mechanism through which Treg cells control inflammatory T cells is through the production of adenosine, which interacts with the adenosine receptor, specifically, A 2A. This receptor is predominately present on inflammatory T cells and inhibits their differentiation [ 80 ].…”