Question

M. tuberculosis can not only infect and subvert macrophages, but also dendritic cells, by similar mechanisms. However, the consequences for immunity are distinct. Using your immunological knowledge, predict the consequences on immunity caused by MTb suppression of phagosome killing in dendritic cells:

Answer 1

Mycobacterium tuberculosis (MTb) is endocytosed by macrophages and dendritic cells. Endocytosis can occur through complement receptor (CR), Fc receptor (FcR), surfactant protein A (Sp-A) receptors etc. Dendritic cell endocytosis is through the specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). The fate of MTb can be:

a) The immune system is able to destroy the bacteria. Hence, the individual doesn’t develop TB. b) The bacilli can multiply and cause primary TB. c) Bacteria can remain in lung in quiescent stage called latent TB.. d) Bacilli can reactivate after a long quiescent stage and cause disease.

Macrophages and Dendritic cells present the MTb antigens to T cells which will then secrete TNF alpha or IFN gamma. This can cause death of the bacilli. DC and macrophages also secrete IL-6 and IL-1 which cause immune cells to reach the site of infection. In macrophages, MTb inhibits the fusion of phagosome and lysosome, thereby inhibiting its killing by the macrophage. Thus, MTb can grow in macrophages. However, infection of DC limits the growth of bacteria, but doesn’t kill it.

In dendritic cells, MTb binds to DC-SIGN and is captured. The intact bacilli are internalized via the mycobacterial cell-wall component ManLAM. This DC-SIGN and ManLAM combination will inhibit DC maturation. MTb can inhibit MHC Class II antigen presentation. However, the surface expression of MHC class II co-stimulatory molecules on surface of DC is normal. Thus. there is a mis-timing of antigen presentation and DC maturation. The phagolysosome maturation is arrested. The activation program proceeds before the DC acquires sufficient antigens of MTb. ManLAM is an activator f Toll like receptor 2 in DC. TLR2 signaling induces production of IL-10, which reduces DC functioning. It is also required for functioning of Treg cells. Even in DC (as in macrophages), there is inhibition of phagolysosome fusion due to no acidification of mycobacterial phagosome. This is possibly through inhibition of the PI3K pathway.

Although phagolysosomes are not formed in DC, there is no killing. However, in contrast to macrophages, the mycobacteria do not grow in DC. The cytokines IL‐12p40 and CCL17 are upregulated in DC (and not chemokine (C‐X‐C motif) ligand 10 (CXCL10), which is in macrophages). CCL17 has a receptor on CD4+CD25+ T‐regulatory cells. Thus, DC seem to have a role in recruiting Treg cells to site of primary infection.

The DC limit the growth of MTb by creating nutrient deprived state. Thus, the bacilli will have anerobic mode of growth. It is possible that the lack of replication of MTb in DC may be advantageous to the bacteria. The bacterial growth inhibition may be a strategy to prevent strong inflammatory response by host immune system, which is caused by destruction of the bacilli. Infection in DC may also be a strategy to form latent infection. Thus, the bacteria may persist in the granuloma for prolonger time and survive the host under extreme condition. MTb may be able to survive in hypoxic conditions and nutrient deprivation in DC, without eliciting an immune response.