Mycobacterium tuberculosis GrpE, A Heat-Shock Stress Responsive Chaperone, Promotes Th1-Biased T Cell Immune Response via TLR4-Mediated Activation of Dendritic Cells

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is an extremely successful pathogen with multifactorial ability to control the host immune response. Insights into the Mtb factors modulating host response are required for the discovery of novel vaccine antigen targets as well as a better understanding of dynamic interactions between the bacterial factors and host cells. Here, we exploited the functional role of Mtb GrpE, a cofactor of heat-shock protein 70 (HSP70), in promoting naïve CD4+/CD8+T cell differentiation toward Th1-type T-cell immunity through interaction with dendritic cells (DCs). GrpE functionally induced DC maturation by up-regulating the expression of cell surface molecules (CD80, CD86, and MHC class I and II) and production of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-12p70) in DCs. These effects of GrpE in DC activation were initiated upon binding to Toll-like receptor 4 (TLR4) followed by activation of downstream MyD88-, TRIF-, MAPK-, and NF-κB-dependent signaling pathways. GrpE-activated DCs displayed an excellent capacity to effectively polarize naïve CD4+ and CD8+ T cells toward Th1-type T-cell immunity with the dose-dependent secretion of IFN-γ and IL-2 together with increased levels of CXCR3 expression. Notably, GrpE-stimulated DCs induced the proliferation of GrpE-specific Th1-type effector/memory CD4+/CD8+CD44highCD62Llow T cells from the spleen of Mtb-infected mice in a TLR4-dependent manner. Collectively, these results demonstrate that GrpE is a novel immune activator that interacts with DCs, in particular, via TLR4, to generate Th1-biased memory T cells in an antigen-specific manner. GrpE may contribute to the enhanced understanding of host-pathogen interactions as well as providing a rational basis for the discovery of new potential targets to develop an effective tuberculosis vaccine.

Clinical Significance of M1/M2 Macrophages and Related Cytokines in Patients with Spinal Tuberculosis

“…The M.tb infection is regulated by both immune and pathogenic factors [15,16]. The research on the body immunity mainly focuses on the regulation of various cytokines on tuberculous granulomas and the function and type of T cells in the development of tuberculous granulomas.…”

Host and Pathogen Communication in the Respiratory Tract: Mechanisms and Models of a Complex Signaling Microenvironment

“…Specifically, TLR2 detection of cell wall components PIM and mannosylated lipoarabinomannan (Man-LAM) result in robust anti-inflammatory responses characterized by decreased secretion of TNF and IL-12p40 and increased secretion of IL-37, respectively ( 115 , 116 ). At the same time, HSP70-cofactor GrpE activates DCs and leads to their subsequent preferential induction of proinflammatory Th1 cells via TLR4 recognition ( 117 ). Additionally, detection of Man-LAM by different macrophage receptors such as the mannose receptor, complement receptors, and DC-SIGN can manipulate induction of proinflammatory responses to reduce local immune cell activation, as well as to inhibit phagosomal maturation inside infected macrophages ( 118 – 120 ).…”

Latest Comprehensive Knowledge of the Crosstalk between TLR Signaling and Mycobacteria and the Antigens Driving the Process

“…In particular, HSP65 was demonstrated to signal exclusively through TLR4 [137]. Mtb GrpE, a cofactor of HSP70, induces the activation and maturation of DCs upon binding to TLR4 and promotes Th1-biased T-cell immune responses, as DCs from TLR4 − / − mice exhibited no response to Mtb GrpE [138]. Similarly, RpfB is another Mtb antigen that binds to TLR4, followed by MyD88/TRIF-dependent signaling and subsequent MAPK and NF-κB activation in DCs [139].…”