IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice.
Resistance to tuberculosis (TB) is dependent on the induction of Ag-specific CD4 Th1 T cells capable of expressing IFN-gamma. Generation of these T cells is dependent upon IL-12p70, yet other cytokines have also been implicated in this process. One such cytokine, IL-27, augments differentiation of naive T cells toward an IFN-gamma-producing phenotype by up-regulating the transcription factor T-bet and promoting expression of the IL-12Rbeta2 chain allowing T cells to respond to IL-12p70. We show that the components of IL-27 are induced during TB and that the absence of IL-27 signaling results in an altered disease profile. In the absence of the IL-27R, there is reduced bacterial burden and an increased lymphocytic character to the TB granuloma. Although the number of Ag-specific CD4 IFN-gamma-producing cells is unaffected by the absence of the IL-27R, there is a significant decrease in the level of mRNA for IFN-gamma and T-bet within the lungs of infected IL-27R(-/-) mice. Ag-specific CD4 T cells in the lungs of IL-27R(-/-) also produce less IFN-gamma protein per cell. The data show that expression of IL-27 during TB is detrimental to the control of bacteria and that although it does not affect the number of cells capable of producing IFN-gamma it does reduce the ability of CD4 T cells to produce large amounts of IFN-gamma. Because IFN-gamma is detrimental to the survival of effector T cells, we hypothesize that the reduced IFN-gamma within the IL-27R(-/-) lung is responsible for the increased accumulation of lymphocytes within the mycobacterial granuloma.
Pearl
John E
JE
Trudeau Institute, Inc., Saranac Lake, NY 12983, USA.
Khader
Shabaana A
SA
Solache
Alejandra
A
Gilmartin
Leigh
L
Ghilardi
Nico
N
deSauvage
Fred
F
Cooper
Andrea M
AM
D000336:Aerosols; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D019281:Dimerization; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009169:Mycobacterium tuberculosis / Q000254:growth & development* / Q000276:immunology*; D021122:Protein Subunits / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology* / Q000517:prevention & control
D000336:Aerosols; C097732:EBI3 protein, human; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D021122:Protein Subunits; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D007371:Interferon-gamma