Immune receptors are a unique family of receptor complexes in cells of the immune system, typically made up of integral membrane proteins of the immunoglobulin (Ig) superfamily that are involved in ligand recognition, associated with other transmembrane signaling proteins that have unique tyrosine-containing motifs in their cytoplasmic tails. The signaling proteins are often positioned close to nonreceptor tyrosine kinases of the SRC family, which possess N-terminal lipid anchors that tether them to the inner leaflet of the plasma membrane. In a few members of the immune receptor family, the receptor consists of a single chain in which the extracellular domain is involved in ligand recognition and the cytoplasmic tail contains tyrosine residues that contribute to signaling.

Three functionally different types of cytoplasmic tyrosine-containing motifs are of particular relevance in the signaling proteins of the immune receptor family. These include an activating motif, an inhibitory motif, and a motif that can either activate or inhibit depending on the cell type and the particular immune receptor. Immunoreceptor tyrosine-based activation motifs (ITAMs) are found in the cytoplasmic tails of receptor-associated proteins that are involved in cell activation and have the sequence YxxL/I(x)6 8YxxL/I, where Y represents a tyrosine residue, L represents leu cine, I represents isoleucine, and x refers to any amino acid. Both tyrosine residues in ITAM motifs can be phosphorylated by SRC family kinases when immune receptors are activated. Tyrosine phosphorylated ITAMs recruit either SYK or ZAP70, which contain tandem SH2 domains that each bind to one of the two phosphorylated YxxL/I motifs of the ITAM. Binding of the SYK or ZAP70 kinase to a phosphorylated ITAM causes a conformational change that activates the kinase, leading to additional signaling events that drive immune cell activation. Some immune receptors inhibit cellular responses and signaling chains in these receptors may contain a slightly different tyrosine-containing motif that is called an immunoreceptor tyrosine-based inhibitory motif (ITIM), which has the consensus sequence V/L/IxYxxL, where V refers to valine. Phosphorylated ITIMs recruit tyrosine phosphatases or inositol lipid phosphatases, enzymes that remove phosphate residues from phosphotyrosine moieties or from certain lipid phosphates and thus counteract ITAM-based immune receptor activation. Certain receptors contain a cytosolic motif called an immunoreceptor tyrosine-based switch motif (ITSM) that has the consensus sequence TxYxxV/I. This motif can sometimes function in an inhibitory fashion and recruit an SH2 domain–containing tyrosine phosphatase, as is the case with the ITSM in the cytosolic tail of PD-1 (Fig. 1). It is called a switch motif because in some receptors (e.g., of the SLAM family) this motif can orchestrate a switch from the binding of a tyrosine phosphatase, SHP2, to binding a tyrosine kinase, such as FYN, depending on the absence or presence, respectively, of an adaptor called SAP (SLAM associated protein). Thus, the ITSM can mediate either an inhibitory or an activating function for the same receptor.

Fig1. Selected members of the immune receptor family. Five selected members of the immune receptor family are depicted. Typically, immune receptors that activate immune cells have separate polypeptide chains for recognition and associated polypeptide chains that contain cytosolic immunoreceptor tyrosine based activation motifs (ITAMs). Examples shown here include the B-cell receptor (BCR), the T-cell receptor (TCR), and the high-affinity receptor for immunoglobulin E (IgE) (FcεRI). Inhibitory receptors in the immune system typically have immunotyrosine-based inhibitory motifs (ITIMs) on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition. FcγRIIB is an inhibitory receptor found on B cells and myeloid cells. PD-1, an inhibitory receptor found on T cells, also has an immunotyrosine-based “switch” motif (ITSM) in its cytoplasmic tail.

General Features of Antigen Receptor Signaling

 Signaling downstream of T- and B-cell antigen receptors is characterized by a similar sequence of events, consisting of the following steps:

 • Receptor ligation by multivalent ligands typically leads to the clustering of receptors and results in activation of an associated nonreceptor kinase of the SRC family. Receptor ligation may also induce the unfolding of the cytoplasmic tail of a polypeptide chain that is part of the receptor. This conformational change may allow previously hidden tyrosine residues of a cytosolic ITAM to become available for phosphorylation by the SRC family kinase.

 • The activated SRC family kinase phosphorylates available tyrosines in the ITAMs of signaling proteins that are part of the receptor complex.

• Two phosphorylated tyrosines in a single ITAM are recognized by SYK or ZAP70 kinases, which contain tandem SH2 domains that each bind to one of the two phosphotyrosines in a phosphorylated ITAM.

• Recruitment of SYK or ZAP70 to the phosphorylated ITAM results in the activation of the kinase and the subsequent tyrosine phosphorylation of multiple adaptor proteins and enzymes that activate distinct signaling pathways down stream of the immune receptor.

Alterations in the strength of TCR and BCR signaling influence the responses of lymphocytes during their development and activation. In other words, the presence of different numbers of activated signaling molecules induced by antigen ligated receptors is interpreted differently by lymphocytes. For example, during lymphocyte maturation, weak antigen receptor signaling is required for survival of clones expressing functional receptors (positive selection), and strong signaling is required to induce apoptosis of clones with self-reactive antigen receptors (negative selection). In mature lymphocytes, strong signaling usually results in clonal expansion and differentiation of naive lymphocytes, and the acquisition of host defense–related functions by effector lymphocytes.

Antigen receptor signaling is fine-tuned and modulated by mechanisms that are unique to this class of receptors.

 • Progressive ITAM use. One of the ways in which the quantity of signal output from antigen receptors might be modulated is the phosphorylation of different numbers of ITAM tyro sines after receptor engagement. The TCR complex has 6 signaling chains and 10 ITAMs and increasing numbers of ITAMs may be phosphorylated with stronger or prolonged binding of antigen to the TCR. The number of ITAMs phosphorylated may therefore provide a cytosolic interpretation of the strength of antigen binding to the TCR (generally reflecting either initial TCR binding avidity or duration of signaling, which may also be influenced by antigen abundance), and this can influence the nature of the cellular response. The BCR complex has only two ITAMs (one each on Igα and Igβ), but because this number increases when multiple BCRs are cross-linked by multivalent antigens, the degree of cross-linking by antigens may determine the number of ITAMs that might be used and thus generate different responses to antigens of differing affinity and valency.

• Increased cellular activation by coreceptors. A coreceptor is a transmembrane signaling protein on a lymphocyte that can facilitate antigen receptor activation by simultaneously binding to the same antigen complex that is recognized by the antigen receptor. Coreceptors are not specific for different antigens but rather bind to nonvariable proteins that associate with diverse antigens. The coreceptor brings with it signaling enzymes linked to its cytoplasmic tail and can thereby facilitate ITAM phosphorylation and activation of the antigen receptor when antigen draws it into the vicinity of the antigen receptor. Coreceptors on T cells are the CD4 and CD8 proteins that demarcate two functionally distinct subsets. Complement receptor type 2 (CR2/CD21) is the coreceptor on B cells.

Modulation of signaling by costimulatory and inhibitory receptors. Antigen receptor signals may, in some circumstances, cooperate with signals from proteins called costimulatory receptors that add yet another level of control to the process of lymphocyte activation. Costimulatory receptors provide so-called second signals for lymphocytes (antigen recognition provides the first signal) and ensure that immune responses are optimally triggered by infectious pathogens and substances that mimic microbes, which are the agents that induce or activate costimulators. Unlike coreceptors, costimulatory receptors on T cells do not bind to the antigens that are recognized by the antigen receptor, but rather to entirely distinct ligands on an antigen-presenting cell (APC) that are induced by pathogens and other potentially dangerous insults. Signal outputs downstream of costimulatory receptors cooperate with the signals derived from the antigen receptor to fully activate lymphocytes. The prototypic costimulatory receptor of T cells is CD28 on T cells, which is activated when bound by the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on APCs.

Key inhibitory receptors in T cells include CTLA-4 and PD-1, and important inhibitory receptors in B cells include CD22 and FcγRIIB, among others. The roles of these inhibitory receptors are discussed later in this chapter.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الخدمية يجري حملة غسل لمحيط العتبة العباسية المقدسة وتنظيفه

العتبة العباسية المقدسة تُعدّ برنامجًا تدريبيًّا لتطوير مهارات ملاكاتها في التعامل مع الزائرين

متحف الكفيل يستعرض قطعًا رخامية توثق مراحل إعمار العتبة العباسية المقدسة في فترة الحكم الملكي

بمشاركة نحو 1000 طالب.. قسم الشؤون الفكرية يختتم جولات برنامج وعي وإدراك في بابل

المزيد

الآخبار الصحية

المشمش المجفف.. كنز صحي للقلب والعظام مع تحذيرات مهمة

خطر خفي في أكياس الشاي يثير مخاوف صحية

نظام غذائي شائع يظهر نتائج واعدة لمرضى السكري

تقنية نانوية روسية تشخص النوبة القلبية خلال 6 دقائق فقط

المزيد

الآخبار التكنلوجية

دراسة جديدة تكشف التركيب الحقيقي لكوكب الأرض

علماء يكتشفون انخفاض صلابة الألماس عند تحويله إلى مقياس نانوي

ثورة في علاج الصمم.. علاج جيني يحقق نتائج استثنائية في استعادة السمع

منهج جديد باستخدام الساعات الذرية يعيد طرح سؤال: ما طبيعة الزمن؟

المزيد

مواضيع ذات صلة

Collectins and Ficolins

Soluble Effector Molecules of Innate Immunity: Pentraxins

Soluble Effector Molecules of Innate Immunity : The Complement System

MHC Genes

Cytokine-Producing Innate Lymphoid Cells

Epithelial Barriers

C-Type Lectins: Receptors for Microbial Carbohydrates

Antigen Capture and the Functions of Antigen-Presenting Cells

Cytosolic DNA Sensors and the STING Pathway

RIG-Like Receptors

Inflammasomes

Antigens