Infection of human dendritic cells with a Mycobacterium tuberculosis sigE mutant stimulates production of high levels of interleukin-10 but low levels of CXCL10: impact on the T-cell response.
The Mycobacterium tuberculosis genome encodes 13 sigma factors. We have previously shown that mutations in some of these transcriptional activators render M. tuberculosis sensitive to various environmental stresses and can attenuate the virulence phenotype. In this work, we focused on extracytoplasmic factor sigmaE and studied the effects induced by the deletion of its structural gene (sigE) in the infection of human monocyte-derived dendritic cells (MDDC). We found that the wild-type M. tuberculosis strain (H37Rv), the sigE mutant (ST28), and the complemented strain (ST29) were able to infect dendritic cells (DC) to similar extents, although at 4 days postinfection a reduced ability to grow inside MDDC was observed for the sigE mutant ST28. After mycobacterium capture, the majority of MDDC underwent full maturation and expressed both inflammatory cytokines, such as tumor necrosis factor alpha, and the regulatory cytokines interleukin-12 (IL-12), IL-18, and beta interferon (IFN-beta). Conversely, a higher level of production of IL-10 was observed in ST28-infected MDDC compared to H37Rv- or ST29-infected cell results. However, in spite of the presence of IL-10, supernatants from ST28-infected DC induced IFN-gamma production by T cells similarly to those from H37Rv-infected DC culture. On the other hand, IL-10 impaired CXCL10 production in sigE mutant-infected DC and, indeed, its neutralization restored CXCL10 secretion. In line with these results, supernatants from ST28-infected cells showed a decreased capability to recruit CXCR3+ CD4+ T cells compared to those obtained from H37Rv-infected DC culture. Thus, our findings suggest that the sigE mutant-induced secretion of IL-10 inhibits CXCL10 expression and, in turn, the recruitment of activated-effector cells involved in the formation of granulomas.
Giacomini
Elena
E
Department of Infectious, Parasitic, and Immuno-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
Sotolongo
Ambar
A
Iona
Elisabetta
E
Severa
Martina
M
Remoli
Maria Elena
ME
Gafa
Valerie
V
Lande
Roberto
R
Fattorini
Lanfranco
L
Smith
Issar
I
Manganelli
Riccardo
R
Coccia
Eliana M
EM
D001426:Bacterial Proteins / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002465:Cell Movement; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000382:microbiology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D012808:Sigma Factor / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001426:Bacterial Proteins; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D020382:Interleukin-18; D012808:Sigma Factor; D014409:Tumor Necrosis Factor-alpha; C111259:sigE protein, Bacteria; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma