Crystal Structure of complete ternary TCR-pMHC-CD4 complex

Multicellular organisms have evolved an intricate immune system which comprises of innate and adaptive immunity.


One of the events critical in order for the adaptive immune system to attack a pathogen is T-cell activation, which occurs as a result of a T-cell recognizing an antigen presented by an antigen-presenting cell (APC) via the major histocompatibility complex (MHC). One peptide-MHC complex (pMHC) must interact with both a T-cell receptor (TCR) as well as a co-receptor (CD4 or CD8, depending on the type of T-cell).

Figure: Interaction of CD8 and CD4 to TCR, Janeway et. al (2008)

Until very recently, many pMHC-TCR complex crystal structures have been published, but not a single one of a full TCR-pMHC-CD4 ternary complex.

This website is mostly based on the paper "Crystal structure of a complete ternary complex of T-Cell receptor, peptide-MHC and CD4'', which presents such a previously unknown structure and discusses certain observations and their implications.

 Biological Significance:

The interaction between a T-cell and an APC triggers a chain of events which are of importance in triggering an immune response.

• Binding of CD4 to antigenic peptide on MHC class II results in increased cytokine production or activation of B cells  by helper T cells which are TH1 and TH2. Cytokines are very important in inter-cellular communication between cells. 
• One well known example is IL-4 which induces class switching of B-cell and up-regulation of MHC class II production. It also antagonises and decreases the production of IL-12 of Th1 cells, macrophages, etc.

• Similarly, the binding of CD8 to antigenic peptide on MHC class I results in increased response of cytotoxic T cells.
•  For example, during hepatitis B virus (HBV) infection, cytotoxic T cells contribute to playing an important pthogenictic role to nearly all of the liver injury associated with HBV infection and, by killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes and also helping eliminate the virus.

• The main function of CD4 and CD8 coreceptors is believed to recruit Lck to TCR-pMHC complex and activate ZAP-70 and continue the downstream signalling. (please refer to the movie above). The movie is basically about the basic mechanism of understood TCR signalling inititation and pathway.

• Objective: Contrary to belief CD4 physically associating with TCR, it is believed that CD4 and TCR possibly interacts indirectly, creating a pseudodimeric TCR for intracellular signalling. . In order to understand a currently controversial topic on mechanism of TCR triggering and on understanding how CD4/CD8 could restrict TCR docking options on pMHC, a clear structure of CD4 bound to TCR-pMHC is needed to clarify!

• We focus on the article on the crystal structure of TCR-pMHC-CD4 complex because although numerous structures of TCR-pMHC complexes have been determined, none has been done on TCR-pMHC-CD4 complex .  Despite some biochemical and functional evidences, from this structure a hypothetical model was brought up and it rules out direct interactions between CD4 and TCR. Many hypothesis has been made on how CD4 could indirectly interact with TCR.