Intrathymic restriction and peripheral expansion of the T-cell repertoire in Omenn syndrome

Mutations in the human RAG genes that impair, but do not abolish, recombina tion activity lead to Omenn syndrome, a severe primary immune deficiency th at is associated with clinical and pathological features of graft-versus-ho st disease and oligoclonal expansion of activated, autologous T cells. We h ave analyzed the mechanisms accounting for peripheral oligoclonality of the T-cell repertoire. Predominance of few T-cell receptor clonotypes (both wi thin TCRAB- and within TCRGD-expressing lymphocytes) is already detectable in the thymus and is further selected for in the periphery, with a differen t distribution of clonotypes in different tissues. These data indicate that oligoclonality of the T-cell repertoire in Omenn syndrome is due both to i ntrathymic restriction and to peripheral expansion. Moreover, the RAG genes defect that causes Omenn syndrome directly affects early stages of V(D)J r ecombination, but does not alter the process of double-strand-break DNA rep air, including N and P nucleotide insertion. (C) 1999 by The American Socie ty of Hematology.