Regulation of immune responses to Mycobacterium tuberculosis secretory antigens by dendritic cells.
Towards elucidating the immune responses induced by antigens from the Mycobacterium tuberculosis (M. tb) RD-1 region, we have been characterizing their interactions with dendritic cells (DCs) and their precursors. We have shown that incubation of bone marrow DC precursors with M. tb antigens induces the differentiation of DC precursors and also the maturation of various DC subsets. While MTSA differentiated DCs were immature, MTSA matured DCs were terminally mature. However, regardless of their maturation status M. tb secretory antigen-activated DCs down-regulated pro-inflammatory T helper cell responses to a subsequent challenge with M. tb cell extract (CE) while increasing regulatory responses. Investigations into the underlying mechanisms showed that stimulation with M. tb CE changed the polarization of antigen-activated DCs from DC1 to DC2. This resulted in secretion of high levels of IL-10 and TGF-beta together with increased surface expression of CD86. Blocking either IL-10 or TGF-beta or CD86 restored Th1 responses to CE antigens. Conversely, treatment of antigen-activated DCs with IL-12 and/or IFN-gamma fully restored Th1 responses of CE antigens. These results indicate that M. tb strategically secretes antigens from infected macrophages to down-regulate pro-inflammatory immune responses at sites of infection.
Latchumanan
Vinoth K
VK
Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Balkhi
Mumtaz Yaseen
MY
Sinha
Aprajita
A
Singh
Balwan
B
Sharma
Pawan
P
Natarajan
Krishnamurthy
K
D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
D000942:Antigens, Bacterial; D051940:B7-2 Antigen; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C072681:Mycobacterium tuberculosis antigens; D018664:Interleukin-12; D007371:Interferon-gamma