Expansion of circulating V gamma 9/V delta 1 T cells in a patient with a syndrome of recurrent fever: evidence for an unusual antigen-driven process leading to selection of recurrent motifs within TCR junctional loops of diverse lengths.

Abstract

Polyclonal expansions of human Vdelta1 T cells have been described in diverse physiopathological situations without strong TCR structural data for an antigen-driven selection. Here, we have analyzed the phenotype and TCR repertoire of gamma delta T cells obtained from the peripheral blood of a 19-year-old patient with a syndrome of recurrent fever, which accounted for up to 40% of CD3(+) T cells and expressed predominantly Vgamma9 and Vdelta1 TCR regions and a memory phenotype. Sequence analysis of Vdelta1-Jdelta1 transcripts derived from peripheral blood lymphocytes (PBL) indicated that, while Vdelta1-Jdelta1 junctional sequences were diverse in length, all but one contained several recurrent motifs at conserved positions from both the 5'- and 3'-ends of the complementarity-determining region (CDR)3 loop. Analysis of gamma delta T cell clones derived from patient PBL demonstrated that Vgamma9(+) but not Vgamma9(-) T cell clones frequently expressed Vdelta1 chains with these characteristics and unveiled a hierarchy between the constraints imposed on the 5'- vs. the 3' motifs of the Vdelta1 CDR3 loops. These results constitute the first strong evidence for a nominal antigen-driven selection of Vdelta1 T cells in vivo and also suggest that the hierarchy of the constraints imposed by antigens respectively on the length and amino acid composition of TCR CDR3 loops differs between alpha beta and gamma delta T cells.