CD3

CD3 refers to a protein complex expressed on the surface of most mature T lymphocytes. It comprises four chains—CD3 gamma (CD3G), CD3 delta (CD3D), CD3 epsilon (CD3E), and the CD3 zeta chain (CD247)—that associate with the T-cell receptor (TCR) to form the TCR-CD3 complex. This complex is essential for surface expression of the TCR and for transmitting activation signals when the TCR recognizes antigenic peptide–MHC complexes. CD3 is widely used as a pan-T cell marker in flow cytometry and immunohistochemistry.

Molecular architecture and signaling: The CD3 chains form heterodimers (CD3ε with CD3γ or CD3δ) together with a CD3ζζ homodimer, assembling the CD3 portion of the TCR complex alongside the TCRαβ or TCRγδ chains. The cytoplasmic tails of CD3 and zeta carry immunoreceptor tyrosine-based activation motifs (ITAMs). Upon antigen engagement, kinases such as Lck phosphorylate ITAMs, leading to recruitment and activation of ZAP-70 and downstream signaling cascades that include calcium flux, PLCγ1 activation, and pathways like MAPK and NF-κB, ultimately promoting T cell activation, proliferation, and differentiation.

Biological role: The CD3 complex is critical for T cell development and function. It stabilizes TCR expression on the cell surface and translates extracellular antigen recognition into intracellular signals. Proper ITAM integrity is essential for effective signaling; defects can impair T cell responses and cause immunodeficiency.

Clinical relevance: CD3 serves as a diagnostic and therapeutic target. It is used to identify T cells in diagnostic immunophenotyping. Anti-CD3 antibodies (such as muromonab-CD3) have been used to prevent organ transplant rejection and treat acute cellular rejection, though they may cause cytokine release syndrome. In cancer immunotherapy, CD3-engaging strategies—such as bispecific antibodies that recruit T cells to tumor cells or CD3-targeted CAR constructs—are under development. CD3 expression is also assessed in T cell leukemias and lymphomas.