Toll-Like Receptors in Adaptive Immunity

The immune (innate and adaptive) system has evolved to protect the host from any danger present in the surrounding outer environment (microbes and associated MAMPs or PAMPs, xenobiotics, and allergens) and dangers originated within the host called danger or damage-associated molecular patterns (DAMPs) and recognizing and clearing the cells dying due to apoptosis. It also helps to lower the tissue damage during trauma and initiates the healing process. The pattern recognition receptors (PRRs) play a crucial role in recognizing different PAMPs or MAMPs and DAMPs to initiate the pro-inflammatory immune response to clear them. Toll-like receptors (TLRs) are first recognized PRRs and their discovery proved milestone in the field of immunology as it filled the gap between the first recognition of the pathogen by the immune system and the initiation of the appropriate immune response required to clear the infection by innate immune cells (macrophages, neutrophils, dendritic cells or DCs, and mast cells). However, in addition to their expression by innate immune cells and controlling their function, TLRs are also expressed by adaptive immune cells. We have identified 10 TLRs (TLR1-TLR10) in humans and 12 TLRs (TLR1-TLR13) in laboratory mice till date as TLR10 in mice is present only as a defective pseudogene. The present chapter starts with the introduction of innate immunity, timing of TLR evolution, and the evolution of adaptive immune system and its receptors (T cell receptors or TCRs and B cell receptors or BCRs). The next section describes the role of TLRs in the innate immune function and signaling involved in the generation of inflammation. The subsequent sections describe the expression and function of different TLRs in murine and human adaptive immune cells (B cells and different types of T cells, including CD4⁺T cells, CD8⁺T cells, CD4⁺CD25⁺T_regs, and CD8⁺CD25⁺T_regs, etc.). The modulation of TLRs expressed on T and B cells has a great potential to develop different vaccine candidates, adjuvants, immunotherapies to target various microbial infections, including current COVID-19 pandemic, cancers, and autoimmune and autoinflammatory diseases.