Shigellaimpairs human T lymphocyte responsiveness by hijacking actin cytoskeleton dynamics and T cell receptor vesicular trafficking

Abstract

Strategies employed by pathogenic enteric bacteria, such as Shigella, to subvert the host adaptive immunity are not well defined. Impairment of T lymphocyte chemotaxis by blockage of polarised edge formation has been reported upon Shigella infection. However, the functional impact of Shigella on T lymphocytes remains to be determined. Here, we show that Shigella modulates CD4+ T cell F‐actin dynamics and increases cell cortical stiffness. The scanning ability of T lymphocytes when encountering antigen‐presenting cells (APC) is subsequently impaired resulting in decreased cell–cell contacts (or conjugates) between the two cell types, as compared with non‐infected T cells. In addition, the few conjugates established between the invaded T cells and APCs display no polarised delivery and accumulation of the T cell receptor to the contact zone characterising canonical immunological synapses. This is most likely due to the targeting of intracellular vesicular trafficking by the bacterial type III secretion system (T3SS) effectors IpaJ and VirA. The collective impact of these cellular reshapings by Shigella eventually results in T cell activation dampening. Altogether, these results highlight the combined action of T3SS effectors leading to T cell defects upon Shigella infection.

CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD

“…The IS is a complex structure composed of spatially segregated substructures whose formation and maintenance is dependent on several intercellular protein/ protein interactions, including CD80-CD28 and particularly ICAM1-LFA-1 at the DC/T cell interface [36][37][38]. The actin cytoskeleton also has a key role in its formation [39], and its perturbation in T cells by Shigella affects their ability to scan B cells efficiently, which reduces cellcell conjugation [40]. Despite the existence of Salmonella effectors that target actin [1], we have not observed an obvious effect of Salmonella on F-actin accumulation in the synaptic region of DCs.…”

The L-DBF vaccine cross protects mice against different Shigella serotypes after prior exposure to the pathogen

“…Pre-exposure resulted in significantly higher IL-6 and lower IFN-γ in the lungs of mice, but there were no notable differences seen for TNF-α, IL-12p70, and IL-1β (data not shown). Although important for B cell priming and differentiation to plasma cells and induction of T cell responses, high IL-6 has been shown to be a major factor in derailing the immune system ( 30 – 32 ). Previous studies have demonstrated the ability of Shigella to impair human T lymphocyte responsiveness ( 31 ).…”

The Immunological Synapse: An Emerging Target for Immune Evasion by Bacterial Pathogens

“…Strong support to this hypothesis has been provided by the finding that Shigella impairs IS assembly by disrupting the polarized recycling of TCR-containing endosomes to the IS through two T3SS effectors, the Rab1 GAP VirA and the Arf/Arl targeting cysteine protease IpaJ ( 77 ). Additionally, we have shown that forced expression of the Salmonella protease GtgE, which cleaves and inactivates Rab29 and Rab8 ( 101 , 102 ), similarly impairs IS assembly by inhibiting two sequential steps in the vesicular transport pathway that regulates polarized TCR recycling to the IS ( 54 ).…”

“…Shigella had been previously shown to directly impair T cell chemotaxis through its T3SS effector IpgD, a lipid phosphatase that hydrolyses PI(4,5)P2, thus preventing leading edge formation in which actin dynamics plays a pivotal role ( 76 ). Recently Samassa and colleagues demonstrated that Shigella promotes actin polymerization in CD4 + T cell through an as yet unidentified T3SS effector which leads to an increase in cell stiffness, thereby impairing the ability of T cells to scan APCs for the presence of specific pMHC and hence affecting the efficiency of T cell:APC conjugate formation, which is sets the stage for IS assembly ( 77 ). Since other bacterial pathogens may exploit their T3SS system to invade, albeit not productively infect, T cells, they might exploit the actin-subverting effectors to similarly affect IS formation.…”