Structural and Biophysical Insights into the Role of CD4 and CD8 in T Cell Activation

Abstract

T cell receptors (TCRs) recognize peptides presented by MHC molecules (pMHC) on an antigen-presenting cell (APC) to discriminate foreign from self-antigens and initiate adaptive immune responses. In addition, T cell activation generally requires binding of this same pMHC to a CD4 or CD8 co-receptor, resulting in assembly of a TCR–pMHC–CD4 or TCR–pMHC–CD8 complex and recruitment of Lck via its association with the co-receptor. Here we review structural and biophysical studies of CD4 and CD8 interactions with MHC molecules and TCR–pMHC complexes. Crystal structures have been determined of CD8αα and CD8αβ in complex with MHC class I, of CD4 bound to MHC class II, and of a complete TCR–pMHC–CD4 ternary complex. Additionally, the binding of these co-receptors to pMHC and TCR–pMHC ligands has been investigated both in solution and in situ at the T cell–APC interface. Together, these studies have provided key insights into the role of CD4 and CD8 in T cell activation, and into how these co-receptors focus TCR on MHC to guide TCR docking on pMHC during thymic T cell selection.

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…MHC, also called H-2 antigens (histocompatibility-2 antigens) in mice and HLA antigens (human-leucocyte-associated antigens) in humans, can be separated into two classes. Class I MHC (MHC-I) are expressed by all cells in our body and bind to TCRs associated with the co-receptor CD8, on CD8 + T cells, while Class II MHC (MHC-II) are only expressed on antigen presenting cells (APC), such as dendritic cells (DC) or macrophages, and bind to TCRs associated with CD4, on CD4 + T cells [194]. After activation, and based on the cytokines they will be exposed to, naïve CD4 + T cells (Th0) can polarize into other subsets such as the classical T-helper 1 (Th1), 2 (Th2), or 17 (Th17), or induced T-regulatory cells (iTreg) [195].…”

An immunology primer for computational modelers

“…CD4 + T cells (also known as “helper cells”) express the CD4 protein on the cell surface. Upon ligation of the TCR to a cognate MHC II, the CD4 protein will also bind to the MHC II molecule [36] (Fig. 3f).…”

T Cell Receptor Engineering and Analysis Using the Yeast Display Platform

“…Among the findings, it has been shown that the variable (V) domains of each chain bind to the specific peptide/MHC ligand in a conserved, diagonal orientation. The structural basis of this invariant orientation is still unclear, but it has been suggested to be due to the: 1) geometry required for the entire T cell complex (αβ TCR, CD3 subunits, and co-receptor CD4 or CD8) to productively engage the pepMHC and to signal the T cell during thymic selection [31, 54], 2) evolutionary pressures that yielded “germline” TCR regions with basal affinity for the helices of MHC molecules [22, 34], or 3) perhaps both [29]. …”