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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Spontaneous or Mycobacterium tuberculosis-induced apoptotic neutrophils exert opposite effects on the dendritic
Mercedes Alemán1, Silvia de la Barrera, Pablo Schierloh
1IIHema, Academia Nacional de Medicina, and Servicio de Tisioneumonología, Hospital Muñiz, Buenos Aires, Argentina. maleman@hematologia.anm.edu.ar
Abstract:
Polymorphonuclear neutrophils (PMN) modulate the adaptive immune response through interactions with immature dendritic cells (iDC) while spontaneous apoptotic neutrophils PMNapo (PMNapo) may have an inhibitory effect on DC functions. We investigate the effect exerted by PMNapo in DC maturation and the role of Mycobacterium tuberculosis (Mtb)-induced PMNapo in the cross-presentation of mycobacterial antigens. We demonstrate that Mtb triggers the maturation of iDC while it is impaired by the presence of PMNapo, which abrogate Mtb-induced expression of costimulatory and HLA class II molecules, reducing IL-12 and IFN-gamma release by DC and partially inhibiting Mtb-driven lymphocyte proliferation. This inhibitory effect is not observed in already Mtb-matured DC, and it involves a direct interaction between DC and PMNapo, as supernatants from PMNapo cultures do not reveal this effect. Although PMNapo do not alter Mtb/DC-SIGN interaction, they affect the intracellular signals leading to DC maturation without requiring their entry into DC. Phagocytosis of Mtb-induced PMNapo by iDC leads to lymphoproliferation, which is significantly reduced by blocking CD36 and not DC-SIGN on iDC. Therefore, cross-presentation of Mtb antigens is taking place. Our findings suggest that the inflammatory milieu is subjected to a fine balance between non-infected and Mtb-induced PMNapo: non-infected PMNapo limiting inflammation and Mtb-induced PMNapo generating a specific immune activity.
Insights
Spontaneously apoptotic neutrophils (PMNapo) inhibit dendritic cell (DC) maturation and Mycobacterium tuberculosis (Mtb) antigen presentation. However, Mtb-induced PMNapo can promote specific immune activity, balancing inflammation.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Polymorphonuclear neutrophils (PMN) interact with immature dendritic cells (iDC) to modulate adaptive immunity.
- Spontaneously apoptotic neutrophils (PMNapo) may inhibit dendritic cell (DC) functions.
Purpose of the Study:
- To investigate the effect of PMNapo on DC maturation.
- To determine the role of Mycobacterium tuberculosis (Mtb)-induced PMNapo in the cross-presentation of Mtb antigens.
Main Methods:
- Investigated Mtb-induced DC maturation in the presence of PMNapo.
- Analyzed the expression of costimulatory and HLA class II molecules on DCs.
- Measured cytokine release (IL-12, IFN-gamma) and lymphocyte proliferation.
- Examined the interaction between DCs and PMNapo, including phagocytosis and blocking of CD36 and DC-SIGN.
Main Results:
- Mtb-induced DC maturation was impaired by PMNapo, reducing costimulatory molecule expression, IL-12/IFN-gamma release, and lymphocyte proliferation.
- PMNapo's inhibitory effect on DC maturation was direct, requiring cell-cell interaction.
- Phagocytosis of Mtb-induced PMNapo by iDCs led to lymphoproliferation, modulated by CD36 but not DC-SIGN.
- Cross-presentation of Mtb antigens was confirmed.
Conclusions:
- Non-infected PMNapo limit inflammation, while Mtb-induced PMNapo generate specific immune activity, fine-tuning the inflammatory response.
- Mtb-induced PMNapo play a dual role in modulating DC function and antigen presentation during infection.
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