B7- protein

B7 is a peripheral membrane protein presented by activated antigen-presenting cells (APC). B7 can generate a costimulatory signal or a co-inhibitory signal upon binding of CD28 or CD152 (CTLA-4) epitopes on T cells to increase or decrease the activity of MHC-TCR signaling between the APC and the T cell. Binding of the B7 protein of APC to CTLA-4 of T cells causes inhibition of T cell activity.

There are two variants of B7 proteins:

• B7-1(CD80)
• and
• B7-2(CD86).

It is not known whether the two protein variants differ significantly from each other. So far, CD80 is found on dendritic cells, macrophages and activated B cells, CD86 (B7-2) on B cells. The epitopes CD28 and CD152 (CTLA-4) expressed by T cells interact with both B7-1 and B7-2.

Costimulation: The activation of the immune system e.g. against an infectious pathogen occurs in several steps:

• The T cell receptor must first interact with the major histocompatibility complex (MHC) surface protein. The CD4 or CD8 proteins on the T cell surface form a complex with the CD3 protein, which can then recognize MHC. This is also known as "signal 1" and its main function is to ensure antigen specificity of T cell activation.
• However, MHC binding itself is not sufficient to generate a T cell response. In fact, the absence of other stimulatory signals leads the T cell into anergy. The costimulatory signal necessary to continue the immune response (signal 2) may come from B7-CD28 and CD40-CD40L interactions.
• When CD40 on the antigen-presenting cell (APC) binds to CD40L(CD154) on the T cell, signals are returned to both the APC and the T cell. The signal from the APC to the T cell, causes the T cell to express CD28 on its surface.
• The T cell thus activated, in turn, causes the antigen-presenting cell to express B7 (either B7.1 or B7.2). It is ultimately the B7-CD28 interaction and binding that additionally directs the T cell to express CTLA-4 (the "Cytotoxic T-Lymphocyte Antigen-4" the competitor for CD28). Since CTLA-4 also binds to B7, this reduces the number of B7 molecules that can bind to CD28.
• B7-CTLA-4 binding suppresses T cell activation. The balance between the opposing signals generated by B7-CD28 and B7-CTLA-4 binding regulates the intensity of the T cell response.

Blockade of CD28 leads to a disruption of T-cell activation. This is a mechanism by which the immune system downregulates T cell activation. T cells can also express the surface protein CTLA-4(CD152) and are thus also able to bind B7. This occurs with twentyfold higher affinity for B7 proteins. However, this binding does not lead to T cell activation!

CTLA-4 knockout mice are unable to stop the immune response and develop a fatal massive lymphocyte proliferation.