Arginase‐dependent suppression by CpG‐ODN plus IFA‐induced splenic myeloid CD11b+Gr1+ cells

The ability of synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG‐ODN) to induce both stimulatory and counter‐regulatory responses offers novel opportunities for using these molecules as immunomodulatory agents in different therapeutic strategies. Here, we investigated the potential of CpG‐ODN to activate the arginase (ARG) enzyme in vivo and focused on the consequences of this activation in T‐cell proliferation. Challenging mice subcutaneously with CpG‐ODN emulsified in incomplete Freund's adjuvant (IFA) induced ARG and reduced T‐cell proliferation associated with CD3ζ chain downregulation. Interestingly, impaired T‐cell expansion correlated with elevated levels of CD11b+Gr1+ myeloid cells localized near T‐cell areas in the spleen. In addition, purified CD11b+ cells obtained from the spleen of CpG‐ODN+IFA‐treated mice exhibited increased ARG activity and ARG I expression along with an augmented [3H]‐l‐arginine uptake. CD11b+ myeloid cells significantly suppressed T‐cell proliferation and CD3ζ chain expression induced by a polyclonal stimulus. Furthermore, these effects could be recovered by the addition of excess l‐arginine or by treatment of CD11b+ cells with a specific ARG inhibitor. This study provides a novel evidence that CpG‐ODN+IFA are able to induce splenic CD11b+ cells with ARG activity, with this population being responsible for the impaired T‐cell proliferation observed after the treatment with CpG‐ODN+IFA. These results underscore a key role of CpG‐ODN on ARG activity in vivo and add support to the growing body of evidence in favor of a counter‐regulatory role for CpG‐ODN in an immune response.