The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation.
Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.
Nguyen
Vu H
VH
Department of Medicine, Stanford University, CA, USA.
Shashidhar
Sumana
S
Chang
Daisy S
DS
Ho
Lena
L
Kambham
Neeraja
N
Bachmann
Michael
M
Brown
Janice M
JM
Negrin
Robert S
RS
D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D018380:Hematopoietic Stem Cell Transplantation; D006566:Herpesviridae Infections / Q000276:immunology / Q000517:prevention & control*; D007111:Immunity, Cellular; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D020127:Recovery of Function / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D013934:Thymectomy; D013950:Thymus Gland / Q000276:immunology / Q000821:virology; D014181:Transplantation Immunology
D016693:Receptors, Antigen, T-Cell, alpha-beta