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.

• Klíčová slova
• Tacrolimus, calcineurin inhibitors, cyclosporine A, monocytes, myeloid cells,
• MeSH
• adaptivní imunita * MeSH
• imunoterapie * MeSH
• interleukin-2 metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• přirozená imunita * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 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.

• Klíčová slova
• Tacrolimus, antifungal response, cyclosporine A, pattern recognition receptor signaling,
• MeSH
• antifungální látky metabolismus   MeSH
• Aspergillus fumigatus účinky léků   MeSH
• C-reaktivní protein metabolismus   MeSH
• chemokiny metabolismus   MeSH
• cyklosporin farmakologie   MeSH
• inhibitory kalcineurinu farmakologie   MeSH
• interleukin-10 metabolismus   MeSH
• lidé MeSH
• monocyty účinky léků   metabolismus   MeSH
• myeloidní buňky účinky léků   metabolismus   MeSH
• myši MeSH
• sekvence nukleotidů MeSH
• sekvenční homologie aminokyselin MeSH
• sérový amyloidový protein metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• THP-1 buňky MeSH
• TNF-alfa metabolismus   MeSH
• transkripční faktory NFATC metabolismus   MeSH
• transport proteinů účinky léků   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antifungální látky MeSH
• C-reaktivní protein MeSH
• chemokiny MeSH
• cyklosporin MeSH
• inhibitory kalcineurinu MeSH
• interleukin-10 MeSH
• PTX3 protein MeSH Prohlížeč
• sérový amyloidový protein MeSH
• TNF-alfa MeSH
• transkripční faktory NFATC MeSH

The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11chighMHCII+ cells (Cnb1 CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3+ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11chighMHCII+ cells to express IL-2. Deleting IL-2 in CD11chighMHCII+ cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin-NFAT-IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.

• MeSH
• antigeny CD11c genetika   imunologie   MeSH
• buňky Th17 imunologie   MeSH
• geny MHC třídy II MeSH
• homeostáza MeSH
• interleukin-2 genetika   imunologie   MeSH
• kalcineurin genetika   imunologie   MeSH
• kolitida genetika   imunologie   MeSH
• lidé MeSH
• myeloidní buňky imunologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• střeva imunologie   MeSH
• Th1 buňky imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD11c MeSH
• interleukin-2 MeSH
• kalcineurin MeSH

The Parkinson's disease-associated protein, Leucine-rich repeat kinase 2 (LRRK2), a known negative regulator of nuclear factor of activated T cells (NFAT), is expressed in myeloid cells such as macrophages and dendritic cells (DCs) and is involved in the host immune response against pathogens. Since, the Ca2+/NFAT/IL-2 axis has been previously found to regulate DC response to the fungus Aspergillus, we have investigated the role played by the kinase LRRK2 during fungal infection. Mechanistically, we found that in the early stages of the non-canonical autophagic response of DCs to the germinated spores of Aspergillus, LRRK2 undergoes progressive degradation and regulates NFAT translocation from the cytoplasm to the nucleus. Our results shed new light on the complexity of the Ca2+/NFAT/IL-2 pathway, where LRRK2 plays a role in controlling the immune response of DCs to Aspergillus.

• Klíčová slova
• Aspergillus, NRON, autophagy, dendritic cell, leucine-rich repeat kinase 2, nuclear factor of activated T cells,
• MeSH
• Aspergillus imunologie   MeSH
• aspergilóza imunologie   mikrobiologie   MeSH
• autofagie imunologie   MeSH
• časosběrné zobrazování MeSH
• dendritické buňky imunologie   ultrastruktura   MeSH
• genový knockdown MeSH
• interakce hostitele a parazita imunologie   MeSH
• interleukin-2 metabolismus   MeSH
• intravitální mikroskopie MeSH
• kationty dvojmocné metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• LRRK2 genetika   imunologie   metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteolýza MeSH
• RNA dlouhá nekódující genetika   imunologie   metabolismus   MeSH
• signální transdukce imunologie   MeSH
• spory hub imunologie   MeSH
• transkripční faktory NFATC metabolismus   MeSH
• transmisní elektronová mikroskopie MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• audiovizuální média MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-2 MeSH
• kationty dvojmocné MeSH
• Lrrk2 protein, mouse MeSH Prohlížeč
• LRRK2 MeSH
• malá interferující RNA MeSH
• NRON long non-coding RNA, mouse MeSH Prohlížeč
• RNA dlouhá nekódující MeSH
• transkripční faktory NFATC MeSH
• vápník MeSH

Myeloid leucocytes mediate host protection against infection and critically regulate inflammatory responses in body tissues. Pattern recognition receptor signalling is crucial for myeloid cell responses to pathogens, but growing evidence suggests an equally potent role for Calcineurin-NFAT signalling in control of myeloid cell function. All major subsets of myeloid leucocytes employ Calcineurin-NFAT signalling during immune responses to pathogens and/or tissue damage, but the influence this pathway exerts on pathogen clearance and host susceptibility to infection is not fully understood. Recent data from experimental models indicate that Calcineurin-NFAT signalling is essential for infection control, and calcineurin inhibitors used in transplantation medicine (including cyclosporine A and tacrolimus) are now being tested for efficacy in a diverse range of inflammatory conditions and autoimmune pathologies. Efforts to repurpose calcineurin inhibitor drugs for new therapeutic applications may yield rapid improvements in clinical outcomes, but the potential impact of these compounds on myeloid cell function in treated patients is largely unknown. Here we discuss Calcineurin-NFAT control of myeloid leucocyte function in the context of recent therapeutic developments and ongoing clinical studies.

• Klíčová slova
• Dectin‐1, TLR4, cyclosporine A, immunosuppression, tacrolimus,
• MeSH
• imunosupresiva terapeutické užití   MeSH
• kalcineurin metabolismus   MeSH
• leukocyty imunologie   MeSH
• lidé MeSH
• signální transdukce * MeSH
• transkripční faktory NFATC metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• imunosupresiva MeSH
• kalcineurin MeSH
• transkripční faktory NFATC MeSH