Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling.
Dendritic cells (DCs) show a remarkable functional plasticity in the recognition of Aspergillus fumigatus and orchestrate the antifungal immune resistance in the lungs. Here, we show that thymosin alpha 1, a naturally occurring thymic peptide, induces functional maturation and interleukin-12 production by fungus-pulsed DCs through the p38 mitogen-activated protein kinase/nuclear factor (NF)-kappaB-dependent pathway. This occurs by signaling through the myeloid differentiation factor 88-dependent pathway, involving distinct Toll-like receptors. In vivo, the synthetic peptide activates T-helper (Th) cell 1-dependent antifungal immunity, accelerates myeloid cell recovery, and protects highly susceptible mice that received hematopoietic transplants from aspergillosis. By revealing the unexpected activity of an old molecule, our finding provides the rationale for its therapeutic utility and qualify the synthetic peptide as a candidate adjuvant promoting the coordinated activation of the innate and adaptive Th immunity to the fungus.
Department of Experimental Medicine and Biochemical Sciences Microbiology Section, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. lromani@unipg.it
Luigina
L
Romani
Francesco
F
Bistoni
Roberta
R
Gaziano
Silvia
S
Bozza
Claudia
C
Montagnoli
Katia
K
Perruccio
Lucia
L
Pitzurra
Silvia
S
Bellocchio
Andrea
A
Velardi
Guido
G
Rasi
Paolo
P
Di Francesco
Enrico
E
Garaci
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D016026:Bone Marrow Transplantation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005260:Female; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000382:microbiology; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D013947:Thymosin; D000077596:Thymalfasin