Hypothesis: TCR signal transduction—A novel tri-modular signaling system

Abstract

Antigenic peptides initiate an immune response in T cells via the T cell receptor (TCR). The TCR itself is widely regarded as one of the most complex receptors in nature, as it is comprised of at least six different subunits, the antigen recognizing TCRα and β chains, and the signal transmitting CD3δɛ, γɛ, and ζ 2 dimers. In order for a signal to be transmitted from the TCR to the cytoplasm, the CD3 chains must “sense” that an antigenic peptide has been presented to the TCRα and β subunits. After accomplishing this, there are a total of 10 different immunoreceptor tyrosine activation motifs (ITAMs) present within the CD3 chains which effectively activate the T cell and hence the immune response. The importance of each CD3 chain and subsequently each ITAM has been the focus of intense research. However, the precise role(s) played by each CD3 chain has remained elusive. Using the immunomodulatory peptide termed core peptide (CP), which is proposed to inhibit TCR activation by disrupting TCR–CD3 interactions, a tri-modular signaling system for T cell activation is proposed. By contrast to the existing two distinct signaling model (ζ 2, CD3ɛγ/ɛδ), in this model each of the three dimers, CD3γɛ, δɛ, and ζ 2, are proposed to act as three separate and distinct signaling modules, performing both specific and redundant functions.