STAT1 expression in dendritic cells, but not T cells, is required for immunity to Leishmania major.
The generation of Th1 responses is important for resistance to intracellular pathogens, including the parasite, Leishmania major. Although IFN-gammaR/STAT1 signaling promotes a Th1 response via the up-regulation of T-bet, the requirement for STAT1 in Th1 cell differentiation remains controversial. Although in some cases Th1 cells develop independently of STAT1, STAT1(-/-) mice fail to develop a Th1 response during L. major infection. However, the interpretation of this result is complicated by the role STAT1 plays in Ag presentation and, more importantly, in elimination of parasites by macrophages, because both defective Ag presentation and increased parasite burden can influence Th cell development. To resolve this issue, we assessed the ability of STAT1(-/-) T cells to become Th1 cells and protect mice against L. major following adoptive transfer into STAT1-sufficient mice. We found that whereas T-bet is critical for the differentiation of protective Th1 cells during L. major infection, IFN-gammaR and STAT1 are dispensable. Given that a STAT1-independent Th1 cell response was generated by STAT1-sufficient APCs, but not by STAT1(-/-) cells, we next addressed whether dendritic cells (DCs) require STAT1 signaling to effectively present Ag. We found that STAT1(-/-) DCs had impaired up-regulation of MHC and costimulatory molecules, and, as a consequence, the absence of STAT1 resulted in reduced Th1 cell priming. Taken together, these results demonstrate that T cell expression of STAT1 is not required for the development of Th1 cells protective against L. major and instead stress the importance of STAT1 signaling in DCs for the optimal induction of Th1 responses.
Johnson
Leanne M
LM
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Scott
Phillip
P
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology; D007111:Immunity, Cellular / Q000235:genetics; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D000096743:Interferon gamma Receptor
D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse