The impact of CD4+Foxp3+ Treg on immunity to murine cytomegalovirus after bone marrow transplantation depends on the peripheral or thymic source of T cell regeneration.
OBJECTIVE
The adoptive transfer of regulatory T cells (Treg) in murine models has been shown to ameliorate graft-versus-host disease while it may preserve the graft-versus-leukemia effect. However, the impact of Treg on infectious immunity after bone marrow transplantation (BMT) is still unclear. Immunocompetence against opportunistic viral infections depends on the kinetics of T cell recovery after BMT through two distinctive processes, i.e. lymphopenia-induced proliferation (LIP) of mature T cells and generation of T cells through thymopoiesis.


METHODS
In this study, we set out to assess the effects of adoptively transferred Treg on T cell regeneration in a homeostatic peripheral T cell expansion model and a thymopoiesis-dependent BMT model, and on murine cytomegalovirus (mCMV) clearance and mortality following mCMV challenge.


RESULTS
Using lymphopenic Rag-2(-/-)γc(-/-) mice that received a limited number of congenic T cells, we demonstrate that adoptively transferred Treg abrogate LIP of T cells. mCMV challenge resulted in a rapid increase of viral load and death in mice that received Treg, but not in controls. In contrast, following syngeneic T cell-depleted BMT in Rag-2(-/-)γc(-/-) mice, adoptively transferred Treg did not delay T cell reconstitution nor suppressed thymic output and had no effect on viral clearance and survival following mCMV-challenge.


CONCLUSIONS
The effect of Treg on T cell-mediated immunocompetence against mCMV early after BMT depends on the relative contribution of peripheral expansion and thymopoiesis to T cell regeneration.
Bruinsma
Marieke
M
Department of Haematology, Erasmus University Medical Center, Rotterdam, The Netherlands. m.bruinsma.1@erasmusmc.nl
Wils
Evert-Jan
EJ
Löwenberg
Bob
B
Cornelissen
Jan J
JJ
Braakman
Eric
E
D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000096:biosynthesis; D002470:Cell Survival; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006566:Herpesviridae Infections / Q000276:immunology*; D038041:Lymphopoiesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000472:pathogenicity / Q000502:physiology*; D012038:Regeneration; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D013950:Thymus Gland / Q000473:pathology; D019562:Viral Load; D014774:Virulence
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse