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Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney–Bone Marrow Transplantation to Induce Transplantation Tolerance
Author(s) -
Sprangers B.,
DeWolf S.,
Savage T. M.,
Morokata T.,
Obradovic A.,
LoCascio S. A.,
Shonts B.,
Zuber J.,
Lau S. P.,
Shah R.,
Morris H.,
Steshenko V.,
Zorn E.,
Preffer F. I.,
Olek S.,
Dombkowski D. M.,
Turka L. A.,
Colvin R.,
Winchester R.,
Kawai T.,
Sykes M.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14251
Subject(s) - foxp3 , immunology , medicine , bone marrow , transplantation , cd8 , t cell , immune tolerance , immune system , transplantation chimera , biology , stem cell , haematopoiesis , microbiology and biotechnology , hematopoietic cell
We examined tolerance mechanisms in patients receiving HLA ‐mismatched combined kidney–bone marrow transplantation ( CKBMT ) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high‐throughput sequencing of T cell receptor‐ β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD 4 non‐Tregs revealed marked early enrichment of Tregs ( CD 3 + CD 4 + CD 25 high CD 127 low Foxp3 + ) in blood that resulted from peripheral proliferation (Ki67 + ), possibly new thymic emigration ( CD 31 + ), and, in one tolerant subject, conversion from non‐Tregs. Among recovering conventional T cells, central memory CD 4 + and CD 8 + cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor‐reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia‐driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT . Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.