The immune system relies on precise molecular signals to initiate a response against threats. A central part of this communication involves structures known as Immunoreceptor Tyrosine-based Activation Motifs, or ITAMs. These motifs are specialized components within immune cells that act as molecular switches. When an immune cell detects danger, ITAMs translate that external detection into an internal signal, setting a defensive reaction in motion.
Defining ITAMs in Immunology
The acronym ITAM stands for Immunoreceptor Tyrosine-based Activation Motif. This name describes a short, conserved sequence of amino acids on the portions of immune cell receptors that sit inside the cell. Their function begins after the receptor has already engaged its target, relaying activation signals from the cell surface to the cell’s interior machinery.
The specific structure of an ITAM is defined by a consensus amino acid sequence: YxxL/I, where Y represents tyrosine, L is leucine, I is isoleucine, and ‘x’ can be any amino acid. This sequence is repeated, appearing twice in tandem, separated by a stretch of 6 to 12 other amino acids. This dual arrangement is a defining feature of its signaling function.
While the exterior portion of a receptor is designed to recognize a specific target, the intracellular segment containing the ITAM is poised to initiate a cascade of events once that recognition occurs.
Key Locations of ITAMs within the Immune System
ITAMs are positioned on receptors across a wide spectrum of immune cells, and their placement dictates which cells can respond to particular threats. They are present in the receptors of both the adaptive immune system, which provides targeted memory, and the innate immune system, which offers an immediate defense.
Cells of the adaptive immune system, T and B lymphocytes, rely on ITAMs. In T cells, the T Cell Receptor (TCR) complex incorporates ITAMs within its associated CD3 signaling subunits. The B Cell Receptor (BCR) complex in B cells contains ITAMs in its Igα and Igβ chains, which are necessary for initiating antibody production.
In the innate immune system, ITAMs are also widespread. Natural Killer (NK) cells have activating receptors that utilize ITAMs to identify and eliminate infected or cancerous cells. Phagocytic cells like macrophages and neutrophils employ ITAM-containing Fc receptors to recognize antibody-coated targets. Mast cells and basophils possess FcεRI receptors loaded with ITAMs that trigger the release of histamine when they bind to antibodies.
How ITAMs Trigger Immune Signals
The process of ITAM signaling begins when a cell’s surface receptors cluster after binding to their specific targets. This clustering brings the ITAMs on the intracellular tails of these receptors close to enzymes called Src-family protein tyrosine kinases (PTKs). In T cells, PTKs include Lck and Fyn, while in B cells, kinases like Lyn, Fyn, and Blk perform this initial step.
These Src-family kinases add a phosphate group to the tyrosine residues within the ITAMs. This event, known as phosphorylation, transforms the ITAMs from a passive sequence into an active docking site. The phosphorylated tyrosines attract other signaling proteins that possess an SH2 domain.
The next proteins to arrive are another class of tyrosine kinases, which bind to the phosphorylated ITAMs. In T cells and NK cells, this role is filled by a kinase called ZAP-70, whereas in B cells and macrophages, a similar kinase named Syk is recruited. The binding of Syk or ZAP-70 to the ITAM activates them.
Once activated, Syk and ZAP-70 act as regulators, setting off multiple downstream signaling pathways. They do this by phosphorylating other proteins, including adaptors that serve as scaffolds to assemble larger signaling complexes, amplifying the initial signal. This cascade activates pathways that increase intracellular calcium and promote cell survival and metabolism.
Impact of ITAM Signaling on Immune Cell Activity
The signaling cascade initiated by ITAMs translates into a wide range of immune cell functions, tailored to the specific cell type. The activation signals that begin at the ITAM docking sites culminate in changes to the cell’s behavior, converting it from surveillance to active defense.
For T lymphocytes, ITAM signaling is the trigger for their activation and differentiation. T cells begin to proliferate rapidly, creating clones specific to the detected antigen. These cells then differentiate into effector cells, such as cytotoxic T lymphocytes that kill infected cells, or helper T cells that produce cytokines to orchestrate the immune response.
In B lymphocytes, ITAM engagement through the B cell receptor leads to their transformation into plasma cells, which are specialized to produce and secrete vast quantities of antibodies. This signaling also drives processes like antibody class switching, allowing B cells to produce different types of antibodies.
Other immune cells exhibit distinct responses. For NK cells, ITAM signaling unleashes their cytotoxic potential, causing them to release granules to destroy target cells. In macrophages and neutrophils, it stimulates phagocytosis, while in mast cells, it causes degranulation, the release of histamine that characterizes an allergic reaction.
The Role of ITAMs in Immune Health and Disease
The regulation of ITAM signaling is important for a healthy immune system that combats pathogens without harming the body. When this process is dysregulated, it can contribute to various diseases.
Failures in ITAM signaling can lead to immunodeficiencies. Genetic defects affecting ITAM-containing receptors or downstream kinases like ZAP-70 can impair immune cell development and activation. This leaves individuals vulnerable to infections, as seen in some forms of Severe Combined Immunodeficiency (SCID).
Conversely, excessive ITAM signaling can contribute to autoimmunity. If ITAM-bearing receptors are stimulated by the body’s own tissues, it can activate self-reactive cells that attack healthy organs, as seen in conditions like rheumatoid arthritis and lupus.
This signaling is also involved in allergies, where overactive signaling in mast cells causes the release of histamine in response to harmless allergens. Because of their role, ITAM signaling pathways are targets for drugs like Syk inhibitors to treat autoimmune diseases and certain cancers.