IL-2 was initially characterized as a T cell growth factor in the 1970s, and has been studied intensively ever since. Decades of research have revealed multiple and diverse roles for this potent cytokine, indicating a unique linking role between adaptive and innate arms of the immune system. Here, we review the literature showing that IL-2 is expressed in a plethora of cell types across the immune system, where it has indispensable functions in orchestrating cellular interactions and shaping the nature and magnitude of immune responses. Emerging from the basic research that has revealed the molecular mechanisms and the complexity of the biologic actions of IL-2, several immunotherapeutic approaches have now focused on manipulating the levels of this cytokine in patients. These strategies range from inhibition of IL-2 to achieve immunosuppression, to the application of IL-2 as a vaccine adjuvant and in cancer therapies. This review will systematically summarize the major findings in the field and identify key areas requiring further research in order to realize the potential of IL-2 in the treatment of human diseases.

• Keywords
• Tacrolimus, calcineurin inhibitors, cyclosporine A, monocytes, myeloid cells,
• MeSH
• Adaptive Immunity * MeSH
• Immunotherapy * MeSH
• Interleukin-2 metabolism   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Immunity, Innate * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Interleukin-2 MeSH

Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-α, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.

• Keywords
• Tacrolimus, antifungal response, cyclosporine A, pattern recognition receptor signaling,
• MeSH
• Antifungal Agents metabolism   MeSH
• Aspergillus fumigatus drug effects   MeSH
• C-Reactive Protein metabolism   MeSH
• Chemokines metabolism   MeSH
• Cyclosporine pharmacology   MeSH
• Calcineurin Inhibitors pharmacology   MeSH
• Interleukin-10 metabolism   MeSH
• Humans MeSH
• Monocytes drug effects   metabolism   MeSH
• Myeloid Cells drug effects   metabolism   MeSH
• Mice MeSH
• Base Sequence MeSH
• Sequence Homology, Amino Acid MeSH
• Serum Amyloid P-Component metabolism   MeSH
• Signal Transduction drug effects   MeSH
• THP-1 Cells MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• NFATC Transcription Factors metabolism   MeSH
• Protein Transport drug effects   MeSH
• Binding Sites MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antifungal Agents MeSH
• C-Reactive Protein MeSH
• Chemokines MeSH
• Cyclosporine MeSH
• Calcineurin Inhibitors MeSH
• Interleukin-10 MeSH
• PTX3 protein MeSH Browser
• Serum Amyloid P-Component MeSH
• Tumor Necrosis Factor-alpha MeSH
• NFATC Transcription Factors MeSH