A novel transmembrane ligand inhibits T cell receptor activation

T lymphocytes (T cells) play essential roles in the adaptive immune system. Each mature T cell expresses one type of functional T cell receptor (TCR). The TCR recognizes antigens bound to the major histocompatibility complex (MHC) in antigen presenting cells. The resulting stimulation signal crosses the transmembrane domain of TCR and initiates downstream signaling cascades. The human immune system relies on TCRs to recognize a variety of pathogens. Normally, TCR can distinguish the self-antigens from pathogenic antigens. However, dysfunction or aberrant expression of TCRs causes different inflammatory and autoimmune diseases, which afflict millions of people annually (Chapter I). Current treatments for TCR dysfunction diseases lack efficacy and often have side effects due to lack of target specificity. Intriguingly, an acidic (low pH) extracellular microenvironment has been found in multiple TCR-associated diseases. Drugs that specifically target tissue acidity are expected to cause fewer side effects. Francisco Barrera and colleagues successfully developed pH-responsive membrane peptides using a rational design approach. This approach introduces pH-responsive residues to the designed peptide, causing an alternation of peptide polarity. As a result, the designed peptide becomes α-helix and inserts into the membranes only at acidic pH (Chapter II). We used this approach to design a pH-responsive peptide based on the transmembrane domain of human TCR, termed PITCR. Our aim was to use this peptide to inhibit TCR activation that causes disease. In agreement with our hypothesis, PITCR interacts with TCR and reduces TCR activation. PITCR allosterically interrupts the receptor changes leading to TCR activation (Chapter III). In addition to the potential therapeutic value, the transmembrane peptide PITCR can also be applied to investigate the transmembrane interaction and dynamics that occur upon TCR activation (Chapter IV).