T cell repertoire development in humans with SCID after nonablative allogeneic marrow transplantation

Transplantation of HLA-identical or haploidentical T cell-depleted allogeneic bone marrow (BM) into SCID infants results in thymus-dependent T cell development in the recipients. Immunoscope analysis of the TCR Vbeta repertoire was performed on 15 SCID patients given BM transplants. Before and within the first 100 days after bone marrow transplantation (BMT), patients' PBMC displayed an oligoclonal or skewed T cell repertoire, low TCR excision circles (TREC) values, and a predominance of CD45RO(+) T cells. In contrast, the presence of high numbers of CD45RA(+) cells in the circulation of SCID patients >100 days post-BMT correlated with active T cell output by the thymus as revealed by high TREC values and a polyclonal T cell repertoire demonstrated by a Gaussian distribution of Vbeta-specific peaks. Ten years after BMT, we observed a decrease of the normal polyclonal T cell repertoire and an increase of a more skewed T cell repertoire. A decline of TREC levels and a decrease in the number of CD45RA(+) cells beyond 10 years after BMT was concomitant with the detection of oligoclonal CD3(+) CD8(+) CD45RO(+) cells. The switch from a polyclonal to a more skewed repertoire, observed in the CD3(+)CD8(+)CD45RO(+) T cell subset, is a phenomenon that occurs normally with decreased thymic output during aging, but not as rapidly as in this patient population. We conclude that a normal T cell repertoire develops in SCID patients as a result of thymic output and the repertoire remains highly diverse for the first 10 years after BMT. The TCR diversity positively correlates in these patients with TREC levels.