Introduction

Aim

To obtain the complete structure of a TCR-pMHC-CD4 ternary complex, this will aid our understanding of the interactions between these three molecules and their individual functions in an immune response.

Background

CD4:
This is a glycoprotein co-receptor present on the surface of T helper cells. It is important for the activation of T helper cells. It provides co-activation once interactions between T cell receptors (TCR) and MHC class II have occured. It is comprised of 4 subunits D1-D4.

Figure 1: Structure of CD4 
D1 domain at the top with D2-D4 below

α/βTCR:

It is a heterodimer of α and β Ig-like domains each with a constant region and a variable region (including 3 hypervariable regions). TCRs mediate the interaction of T helper cells (Th) with APCs via binding antigen specific MHC class II molecules on the cell surface. The α variable region dominates peptide recognition and it interacts with MHCIIβ1 domain. Binding of TCRs to MHCII results in downstream signalling via CD3 ITAMs and Lck, resulting in specific cytokine secretion. 

Figure 2: X-ray structure of TCR with β subunit (right) and α subunit (left)
 Cα: green; Vα: blue; Cβ: red; Vβ: yellow 

MHC class II:
It is found of the surface of APCs and lymphocytes. This molecule is a heterodimer of 2α and 2β subunits expressed by HLA-D genes. These molecules have antigen binding cleft which allows the antigen to be exposed on the cell surface to other immune cells such as Th cells. The antigen specific TCRs on the Th cells will then bind to the MHCII and initiate signalling pathway activation within the Th cell. 

Figure 3: X-ray structure of MHC class II HLA-DR1
with α chain in yellow and green and β chain in red and orange

What we know

• CD4-MHC interactions have been proven to increase cytokine production by Th cells.
• CD4 is required to recruit the Src Tyrosine Kinase Lck. This promotes phosphorylation of ITAMs (CD3) upon TCR-pMHC binding.
• The structure of the TCR-pMHC has been determined by x-ray crystallography.
• The structure of unbound CD4 has also been determined by x-ray crystallography (shown above)

What we don't know

• The structure of the TCR-pMHC-CD4 ternary complex 
• How CD4 interacts with the TCR-pMHC
• How the ternary complex formation leads to downstream signalling involving CD3 and Lck