Development of protective immunity against cutaneous leishmaniasis is dependent on STAT1‐mediated IFN signaling pathway

• Published in: European journal of immunology 2003-07, Vol.33 (7), p.1799-1805
• Main Authors: Rosas, Lucia E., Keiser, Tracy, Pyles, Ryan, Durbin, Joan, Satoskar, Abhay R.
• Format: Article
• Language: English
• Subjects: Animals; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Immunity - genetics; Interferons - immunology; Interferons - metabolism; Leishmania; Leishmania major - immunology; Leishmaniasis, Cutaneous - immunology; Mice; Mice, Inbred C57BL; Nitric Oxide - metabolism; Signal Transduction - immunology; STAT1; STAT1 Transcription Factor; Th1/Th2 response; Trans-Activators - genetics; Trans-Activators - immunology; Trans-Activators - metabolism
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200323163

Although STAT1‐dependent signaling mediates biological functions of IFN‐α/β and IFN‐γ, recent reports indicate that STAT1‐independent IFN signaling also regulates expression of several genes. To determine the roles of STAT1‐dependent and ‐independent IFN signaling in the regulation of immunity during cutaneous leishmaniasis, we studied the course of Leishmania major infection in resistant C57BL/6 mice lacking the STAT1 gene. While L. major‐infected STAT1+/+ mice resolved their lesions, STAT1–/– mice developed large lesions containing significantly more parasites. Moreover, the inability of STAT1–/– mice to control L. major infection was due to the lack of Th1 development associated with reduced production of IL‐12, IFN‐γ and nitric oxide. Although STAT1–/– mice produced more IL‐4 and total IgE than STAT1+/+ mice later during infection, these differences were not significant. Nevertheless, at these time points lymph node cells from STAT1–/– mice produced significantly more IL‐10. Finally, STAT1–/– mice were also susceptible to low dose L. major infection. Thesefindings demonstrate that STAT1‐mediated IFN signaling is indispensable for the development of protective immunity against cutaneous L. major infection. Moreover, they also suggest that the protective role of STAT1‐mediated signaling is due to its ability to induce Th1 development during infection with this parasite.