Insights into the Relationship between Toll Like Receptors and Gamma Delta T Cell Responses

Abstract

The tumor microenvironment is an important aspect of cancer biology that contributes to tumor initiation, tumor progression and responses to therapy. The composition and characteristics of the tumor microenvironment vary widely and are important in determining the anti-tumor immune response. Successful immunization requires activation of both innate and adaptive immunity. Generally, immune system is compromised in patients with cancer due to immune suppression, loss of tumor antigen expression and dysfunction of antigen presenting cells (APC). Thus, therapeutic immunization leading to cancer regression remains a significant challenge. Certain cells of the immune system, including dendritic cells (DCs) and gamma delta (γδ) T cells are capable of driving potent anti-tumor responses. The property of MHC-unrestricted cytotoxicity, high potential of cytokine release, tissue tropism and early activation in infections and malignant disease makes γδ T cells as an emerging candidate for immunotherapy. Various strategies are being developed to enhance anti-tumor immune responses of γδ T cells and DCs one of them is the use of novel adjuvants like toll like receptors (TLR) agonists, which enhance γδ T cell function directly or through DC activation, which has ability to prime γδ T cells. TLR agonists are being used clinically either alone or in combination with tumor antigens and has shown initial success in both enhancing immune responses and eliciting anti-tumor activity. TLR activated γδ T cells and DCs nurture each other’s activation. This provides a potent base for first line of defense and manipulation of the adaptive response against pathogens and cancer. The available data provides a strong rationale for initiating combinatorial therapy for the treatment of diseases and this review will summarize the application of adjuvants (TLRs) for boosting immune response of γδ T cells to treat cancer and infectious diseases and their use in combinatorial therapy.

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

“…Thus, restoration of normal functioning of host DCs is very important to prevent immunoparalysis or immunosuppression observed in septic patient and further to prevent the patients recovering from sepsis to catch the severe secondary infection. This can be better understood by studying the TLR mediated regulation of DCs as TLR agonists have shown an important improvement in survival of animals suffering from acute pneumonia after hemorrhagic shock [192,193]. TLR agonist treatment might have prevented the generation of tolerogenic DCs or prevented the release of TGF-β from these tolerogenic DCs via increased expression of MHC class II molecules and co-stimulatory receptors that is CD80 and CD86 on DCs [191][192][193].…”

“…This can be better understood by studying the TLR mediated regulation of DCs as TLR agonists have shown an important improvement in survival of animals suffering from acute pneumonia after hemorrhagic shock [192,193]. TLR agonist treatment might have prevented the generation of tolerogenic DCs or prevented the release of TGF-β from these tolerogenic DCs via increased expression of MHC class II molecules and co-stimulatory receptors that is CD80 and CD86 on DCs [191][192][193]. Thus, regulation of TLR mediated function of DCs plays an important role in the pathogenesis of both infectious and inflammatory diseases and their outcome in terms of survival.…”

The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes

“…The expression of TLR3 has been observed in a number of human tissues including placenta, pancreas, lung, liver, heart, lymph nodes and brain [43]. TLR3 is usually expressed intracellularly in various human and mouse immune cells including T cells, macrophages, DCs, natural killer cells and γδ T cells [44, 45]. TLR3 binds viral dsRNA and induces downstream innate immune responses through a MyD88-independent but TRIF-dependent pathway, unlike the other TLRs [46].…”

Harnessing γδ T Cells as Natural Immune Modulators

“…The expression of pathogenassociated molecular pattern receptors has been detected on γδ T cells. These include another lectin receptor, dectin-1, a receptor for fungal, plant, and bacterial-derived polysaccharides [37,38]; the TLRs [20,39]; CD36 [40]; scavenger receptors [41]; and NOD-like receptors [42]. Though not a focus of this chapter, γδ T cells also express a variety of receptors that downregulate their function.…”