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 V beta 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 V beta-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.
Sarzotti
Marcella
M
Department of Immunology, Medicine, and Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. msarzott@duke.edu
Patel
Dhavalkumar D
DD
Li
Xiaojing
X
Ozaki
Daniel A
DA
Cao
Shui
S
Langdon
Scott
S
Parrott
Roberta E
RE
Coyne
Katherine
K
Buckley
Rebecca H
RH
D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000235:genetics / Q000378:metabolism; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008137:Longitudinal Studies; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D011184:Postoperative Period; D011300:Preoperative Care; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017493:Leukocyte Common Antigens