The molecular assembly of the marsupial {gamma}{mu} T cell receptor defines a third T cell lineage

In non-eutherians, a third type of T cell

The two established T cell lineages found in jawed vertebrates use either an αβ or a γδ T cell receptor (TCR) to detect antigens. Recently, another type of TCR chain (TCRµ) was found in marsupials and monotremes. Morrissey et al. analyzed T cells from the gray short-tailed opossum and uncovered a third lineage resident in the spleen that uses a γµ TCR (see the Perspective by Criscitiello). The authors then characterized the crystal structures of two different γµ TCRs, which exhibited an architecture distinct from αβ or γδ TCRs in which a highly diverse, unpaired immunoglobulin-like variable domain was predicted to be the major antigen recognition determinant. Like camelid VHH and shark IgNAR antibodies, γµ TCRs could potentially inform future nanobody development.

Science, this issue p. 1383; see also p. 1308

Abstract

αβ and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γμTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vμ-Vμj-Cμ) μ-chain. γμTCRs were characterized by restricted diversity in the Vγ and Vμj domains and a highly diverse unpaired Vμ domain. Crystal structures of two distinct γμTCRs revealed the structural basis of the association of the γμTCR heterodimer. The Vμ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3μ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γμTCR.

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