Immune Cell Signaling

Innate immune signaling refers to the complex network of pathways and mechanisms by which the body's immune system detects pathogens and initiates an immediate immune response against them.

Innate immune signaling is mediated by germline-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). These germline-encoded pattern-recognition receptors include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs), AIM2-like receptors (ALRs), and C-type lectin receptors (CLRs). They trigger the activation of inflammasome signaling pathways, including NF-κB and type I interferon (IFN), which then contribute to the production of proinflammatory and antiviral cytokines, and eventually lead to the activation of adaptive immune responses (1, 2).

The innate immune system is the host's first line of defense, providing immediate detection and protection against pathogens. It triggers the development of the adaptive immune response, which produces a targeted, accurate, and long-lasting response (3).

Dysregulated innate immune signaling can lead to increased susceptibility to severe and recurrent infections and inappropriate immune system activation, resulting in autoimmune diseases and chronic inflammation (3, 4).

Adaptive immune signaling pathways activate and regulate the adaptive immune system, consisting of T cells and B cells.  When the innate immune response is unable to clear a new infection, adaptive immunity comes into play as the second line of defense. It elicits antibody responses and cell-mediated immune responses (5).

B cells are crucial to antibody responses. A B cell is activated when the targeted antigens bind to its B cell receptors. This triggers the release of cytokines that attract other immune cells and the release of antibodies into the blood and other body fluids. These antibodies bind specifically to the target antigens to prevent them from binding to receptors on host cells. Antibody binding to invading pathogens also facilitates their recognition by phagocytic cells that eliminate them.

In cell-mediated immune response, T cells act against a foreign antigen on the surface of a host cell by, for example, destroying the infected host cell with viral antigens on its surface, thereby preventing viral replication (5). 

The primary intracellular pathways involved in adaptive immunity are T-cell receptor and B-cell receptor signaling (6).

B cell receptor signaling is activated when an antigen binds to the B-cell receptor. This activation, in turn, triggers a sequence of intracellular events that lead to the internalization of the antigen (7). The internalized antigen is then processed and presented to T cells. B-cell receptor (BCR) signaling is necessary for B-cell development and adaptive immunity. Dysregulated B cell signaling significantly contributes to tumor survival in cancers including B-cell non-Hodgkin lymphomas (B-NHLs) (8).

T cell receptor signaling is activated when the T cell receptor binds to the antigenic peptide. Upon T-cell activation, changes occur at the plasma membrane, cytoplasm, and nucleus that result in T cells undergoing clonal expansion and differentiation, enabling them to become effector cells. T cell receptor signaling plays a crucial role in T cell development, activation, and immune tolerance. However, when T-cell receptor signaling is dysregulated, it can lead to anergy or autoimmunity (9).Other pathways involved in adaptive immunity include toll-like receptor signaling, CD28 costimulatory signaling, and CD40 signaling. 

Cytokines bind to specific receptors on target cells and activate downstream signaling events that lead to the expression of genes , including JAK/STAT and MAPK signaling. Cytokines function via these signaling pathways to regulate cell growth, development, and survival. Cytokines also modify cell behavior in the tissue surroundings, which results in improved immune responses (11).

Mutations in cytokines, cytokine receptors, and signaling pathways are responsible for many primary immunodeficiency syndromes. Excessive cytokine production or responsiveness can lead to the development of autoimmune and inflammatory diseases. Hence, cytokines are important targets in developing monoclonal antibodies and other therapeutic molecules. 

Immune system cells communicate with each other through secreted cytokines. This communication can happen in three different ways, depending on the location and identity of the cell receiving the signal. A cell signaling to self is called autocrine signaling. If the cell signals to neighboring cells, it is called paracrine signaling. Signaling to a distant cell through the bloodstream is called endocrine signaling (11).

Signaling pathways involved in immune cell signaling include cGAS–STING, NF-kB, JAK/STAT, and TNF signaling pathways.