Costimulatory signals are generated by receptors that recognize ligands on APCs and cooperate with TCR signals to promote activation of the T cells. The two-signal hypothesis for T-cell activation. The response by the TCR complex to MHC and peptide on an APC is referred to as signal 1 and the response to costimuators is signal 2. T cells are fully activated only when a foreign peptide bound to an MHC molecule is recognized in the context of activation of the innate immune system by a pathogen or some other cause of inflammation. The best-defined costimulatory ligands represent the danger signals induced on APCs by microbes. Thus, recognition of foreign antigens must be combined with a sense of danger for optimal T-cell activation to occur.
The CD28 Family of Costimulatory Receptors
The major costimulators for T lymphocytes are a pair of related proteins, called B7-1 (CD80) and B7-2 (CD86), which are expressed on activated dendritic cells and other APCs and bind to the CD28 receptor on T cells. The CD28 molecule is an important costimulatory receptor for delivery of second signals for T-cell activation. The biologic roles of the B7 and CD28 protein families are discussed in Chapter 9. Another activating receptor of the CD28 family is a molecule called inducible costimulator (ICOS), which plays an important role in T follicular helper cell development.
The CD2/Signaling Lymphocytic Activation Molecule Family of Costimulatory Receptors
Proteins other than CD28 family members also contribute to T-cell activation and differentiation. One family of proteins that plays a role in the activation of T cells and NK cells is structurally related to a receptor called CD2. In human T cells, CD2 functions both as an intercellular adhesion molecule and as a signal transducer.
A distinct subgroup of the CD2 family of proteins is known as the SLAM (signaling lymphocytic activation molecule) family. SLAM proteins, like all members of the CD2 family, are integral membrane proteins that contain two extracellular Ig domains and a long cytoplasmic tail. The cytoplasmic tail of SLAM proteins, but not of CD2, contains an ITSM that facilitates signaling.
The extracellular Ig domains of SLAM are involved in homophilic interactions. SLAM on a T cell can interact with SLAM on a dendritic cell and, as a result, the cytoplasmic tail of SLAM may deliver signals to T cells. The ITSM motif binds to an adaptor protein called SAP, and the latter forms a bridge between SLAM and FYN (a SRC family kinase that is also physically linked to CD3 proteins in T cells). SLAM and other members of the SLAM family function as costimulatory receptors in T cells, NK cells, and some B cells. mutations in the SH2D1A gene encoding SAP are the cause of a disease called X-linked lymphoproliferative syndrome (XLP).
An important member of the SLAM family in NK cells, CD8+ T cells, and γδ T cells is called 2B4. Like SLAM, the cytoplasmic tail of 2B4 contains ITSM motifs, binds to the SAP adaptor protein, and induces activating signals by recruiting FYN. Defective 2B4 signaling contributes to the immune deficit in patients with XLP syndrome.
