CD28

This entry represents domains with an immunoglobulin-like (Ig-like) fold, which consists of a beta-sandwich of seven or more strands in two sheets with a Greek-key topology. Ig-like domains are one of the most common protein modules found in animals, occurring in a variety of different proteins. These domains are often involved in interactions, commonly with other Ig-like domains via their beta-sheets []. Domains within this fold-family share the same structure, but can diverge with respect to their sequence. Based on sequence, Ig-like domains can be classified as V-set domains (antibody variable domain-like), C1-set domains (antibody constant domain-like), C2-set domains, and I-set domains (antibody intermediate domain-like). Proteins can contain more than one of these types of Ig-like domains. For example, in the human T-cell receptor antigen CD2, domain 1 (D1) is a V-set domain, while domain 2 (D2) is a C2-set domain, both domains having the same Ig-like fold [].

Domains with an Ig-like fold can be found in many, diverse proteins in addition to immunoglobulin molecules. For example, Ig-like domains occur in several different types of receptors (such as various T-cell antigen receptors), several cell adhesion molecules, MHC class I and II antigens, as well as the hemolymph protein hemolin, and the muscle proteins titin, telokin and twitchin.

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable; IPR013106), C1-set (constant-1; IPR003597), C2-set (constant-2; IPR008424) and I-set (intermediate; IPR013098) []. Structural studies have shown that these domains share a common core Greek-key beta-sandwich structure, with the types differing in the number of strands in the beta-sheets as well as in their sequence patterns [].

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system [].

Ig-like domains can be classified according to the number of beta strands. The V-type is antibody variable domain-like, and has two extra beta strands over the classical C1-type Ig-like domain. This subfamily includes Ig variable domains, myelin membrane adhesion molecules, T cell surface glycoproteins, junction adhesion molecules (JAM), coxsackie virus and adenovirus Car receptors, and viral haemagglutinin.

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable; IPR013106), C1-set (constant-1; IPR003597), C2-set (constant-2; IPR008424) and I-set (intermediate; IPR013098) []. Structural studies have shown that these domains share a common core Greek-key beta-sandwich structure, with the types differing in the number of strands in the beta-sheets as well as in their sequence patterns [].

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system [].

This entry represents the V-set domains, which are Ig-like domains resembling the antibody variable domain. V-set domains are found in diverse protein families, including immunoglobulin light and heavy chains; in several T-cell receptors such as CD2 (Cluster of Differentiation 2), CD4, CD80, and CD86; in myelin membrane adhesion molecules; in junction adhesion molecules (JAM); in tyrosine-protein kinase receptors; and in the programmed cell death protein 1 (PD1).

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable; IPR013106), C1-set (constant-1; IPR003597), C2-set (constant-2; IPR008424) and I-set (intermediate; IPR013098) []. Structural studies have shown that these domains share a common core Greek-key beta-sandwich structure, with the types differing in the number of strands in the beta-sheets as well as in their sequence patterns [].

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system [].

This subfamily includes:

• Cell surface receptors containing an immunoglobin domain.
• Killer cell inhibitory receptors.
• Oprin a snake venom metalloproteinase inhibitor from Didelphis marsupialis (Southern opossum) [], which belongs to MEROPS inhibitor family I43, clan I- [].
• Oprin homologues.

Antigen (Ag) recognition by the T cell receptor (TCR) induces activation of T lymphocytes. However, TCR-mediated signals alone are insufficient for efficient T cell activation, and additional co-stimulatory signals are required. One of the most important surface molecules that delivers co-stimulatory signals for T cells is CD28. The human T lymphocyte Ag CD28 (Tp44) is a homodimeric 90kDa glycoprotein expressed on the surface of the majority of human peripheral T cells and lymphocytes. Stimulation of CD4+ T cells in the absence of CD28 co-signalling causes impaired proliferation, reduced cytokine production and altered generation of helper T cell subsets. Co-stimulation via CD28 promotes T cell viability, clonal expansion, cytokine production and effector functions, while also regulating apoptosis of activated T cells, suggesting its importance in regulating long-term T cell survival [].

Ligands for CD28 and the structurally related CTLA-4 (CD152) are the molecules B7.1 (CD80) and B7.2 (CD86). B7.1 and B7.2 are expressed on professional antigen presenting cells (APCs) and their expression is up-regulated during an immune response. Ligation of CD28 by its natural ligands results in tyrosine phosphorylation at a YMNM motif within its cytoplasmic tail. The phosphorylated motif subsequently interacts with the Src homology 2 domain in the p85 regulatory subunit of P13K, activating the p110 catalytic subunit. One of the P13K-dependent downstream targets, resulting from the antibody cross-linking of CD28, is the phoshporylation and activation of Akt (or PKB). Constitutively active Akt is able to substitute for CD28 signals, and stimulates IL-2 production when introduced into mature CD28-deficient cells. Another molecule affected by CD28 stimulation is the proto-oncogene Vav, which acts as a guanine-nucleotide exchange factor for Rac and CDC42, allowing these molecules to switch from the inactive GDP- bound state to the active GTP-bound state [].

Another interesting feature of CD28, is its ability to induce expression of PDE7, a cAMP phosphodiesterase, thus reducing cellular cAMP levels. cAMP has been reported to affect nearly every pathway important for lymphocyte activation, leading to inhibition of T cell proliferation. Specifically, increased intracellular cAMP has been implicated in the induction of T cell anergy, a non-responsive state that occurs after T cells are stimulated through TCR/CD3 in the absence of co-stimulation. This can have therapeutic implications, in that blockage of CD28 co-stimulation can be profoundly immunosuppressive, preventing induction of pathogenic T cell responses in autoimmune disease models, and allowing for prolonged acceptance of allografts in models of organ transplantation [].

Finally, CD28 co-stimulation directly controls T cell cycle progression by down-regulating the cdk inhibitor p27kip1, which actually integrates mitogenic MEK and P13K-dependent signals from both TCR and CD28 [].