Chapter 11 Benchmarking

T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4

“…In particular, CD4 mutants that fail to interact with pMHCII (D2 mutations) or p56 lck (cytoplasmic tail mutants) surprisingly restore antigen responsiveness in the 3A9 T cell hybridoma system. Such restoration is dependent on the D3-D4 module, as shown by additional mutagenesis studies (17). Nevertheless, BIAcore analysis failed to reveal any measurable affinity between the CD4 ectodomain and the TCR ␣␤ heterodimer.…”

“…Additional studies raise the possibility that the CD4 D3-D4 module can interact with the T cell receptor (16,17). In particular, CD4 mutants that fail to interact with pMHCII (D2 mutations) or p56 lck (cytoplasmic tail mutants) surprisingly restore antigen responsiveness in the 3A9 T cell hybridoma system.…”

“…The extracellular rod-like segment of CD4 consists of four concatamerized Ig-like domains (D1-D4), a single transmembrane-spanning segment, and a short cytoplasmic tail (7-10). The membrane distal D1 and D2 domains bind to the nonpolymorphic ␤2 domain of MHC class II molecules, whereas the membrane proximal D3-D4 module is thought to be involved in both CD4 oligomerization and TCR interaction (11)(12)(13)(14)(15)(16)(17). During antigen recognition of peptides bound to MHC class II molecules (pMHCII), CD4 and TCR colocalize, interacting with the same pMHCII molecule (18 -20).…”

Efficient CD4 binding and immunosuppressive properties of the 13B8.2 monoclonal antibody are displayed by its CDR‐H1‐derived peptide CB11

“…The CD4 molecule plays a key role both in the MHC class II‐restricted immune response and the human immunodeficiency virus infection process by acting as a receptor either for the TcR–antigen engagement complex or for the envelope glycoprotein gp120 of HIV [7,9,55,56]. In these two cases, CD4 has been demonstrated to induce signal transduction leading to T cell activation [12,19,21,22].…”

“…CD4 is composed of four extracellular domains (D1–D4), which share homology with the immunoglobulin V κ region [3,4], a transmembrane portion and a cytoplasmic tail non‐covalently associated with the protein tyrosine kinase p56 lck [5]. The CD4 molecule acts as co‐receptor for the major histocompatibility complex (MHC) class II and is a molecular partner for the T cell receptor (TcR) [6–9]. This trimolecular complex is critical for optimal activation of T cells [10–12].…”