Treatment of post-transplant patients with immunosuppressive drugs targeting the calcineurin-nuclear factor of activated T cells (NFAT) pathway, including cyclosporine A or tacrolimus, is commonly associated with a higher incidence of opportunistic infections, such as Aspergillus fumigatus, which can lead to severe life-threatening conditions. A component of the A. fumigatus cell wall, β-glucan, is recognized by dendritic cells (DCs) via the Dectin-1 receptor, triggering downstream signaling that leads to calcineurin-NFAT binding, NFAT translocation, and transcription of NFAT-regulated genes. Here, we address the question of whether calcineurin signaling in CD11c-expressing cells, such as DCs, has a specific role in the innate control of A. fumigatus. Impairment of calcineurin in CD11c-expressing cells (CD11ccrecnb1loxP) significantly increased susceptibility to systemic A. fumigatus infection and to intranasal infection in irradiated mice undergoing bone marrow transplant. Global expression profiling of bone marrow-derived DCs identified calcineurin-regulated processes in the immune response to infection, including expression of pentraxin-3, an important antifungal defense protein. These results suggest that calcineurin inhibition directly impairs important immunoprotective functions of myeloid cells, as shown by the higher susceptibility of CD11ccrecnbloxP mice in models of systemic and invasive pulmonary aspergillosis, including after allogeneic bone marrow transplantation. These findings are relevant to the clinical management of transplant patients with severe Aspergillus infections.

Center for Translational Medicine International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Department of Biological Sciences National University of Singapore Singapore

Department of Experimental Medicine University of Perugia Perugia Italy

Emerging Infectious Diseases Programme Duke NUS Singapore

National University of Singapore Graduate School for Integrative Sciences and Engineering National University of Singapore Singapore

Singapore Immunology Network Biopolis Singapore

References provided by Crossref.org

Immunosuppression Affects Neutrophil Functions: Does Calcineurin-NFAT Signaling Matter?

NFAT signaling in human mesenchymal stromal cells affects extracellular matrix remodeling and antifungal immune responses

Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes

Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis

Calcineurin-NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy