TCR

T cell receptor (TCR) is a membrane-bound protein complex expressed on the surface of T lymphocytes. It recognizes peptide antigens presented by major histocompatibility complex (MHC) class I or class II molecules on antigen-presenting cells. Most T cells carry an alpha-beta (αβ) TCR, while a smaller subset expresses a gamma-delta (γδ) TCR. The antigen-binding site is formed by the variable regions of the two chains and is generated by somatic V(D)J recombination, yielding vast diversity through junctional choices and nucleotide additions.

The TCR is associated with the CD3 signaling complex, comprising multiple chains that contain immunoreceptor tyrosine-based activation motifs (ITAMs). Engagement of the TCR with a peptide-MHC complex, often with co-receptors such as CD4 (for MHC II) or CD8 (for MHC I), triggers intracellular signaling. This leads to calcium flux and activation of signaling pathways including MAPK, NFAT, and NF-κB, ultimately resulting in T cell activation, proliferation, and effector function. Full activation typically requires additional co-stimulatory signals, such as CD28 engagement.

During T cell development in the thymus, TCR gene rearrangement is driven by RAG1/2 enzymes. Thymocytes undergo positive selection for the ability to recognize self-MHC and negative selection to eliminate strongly self-reactive cells, shaping a repertoire that maintains self-tolerance in the periphery.

Diversity in TCRs enables recognition of a wide range of antigens. αβ T cells constitute the majority and mediate adaptive immunity, while γδ T cells display more innate-like properties and participate in mucosal and stress-related responses.

In clinical research and therapy, TCRs are being exploited in TCR-engineered T cell therapies to target tumor-associated peptide-MHC complexes. Potential risks include off-target reactivity and mispairing with endogenous TCR chains, which ongoing efforts aim to minimize.