Endotoxin hyperresponsiveness upon CD4+ T cell reconstitution in lymphopenic mice: control by natural regulatory T cells.
Natural CD4(+)CD25(+) regulatory T cells (nTreg) have been shown to control graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). Herein, we considered the possibility that the beneficial action of nTreg upon immune reconstitution in lymphopenic hosts involves dampening of the inflammatory response induced by bacterial products. We first observed that transfer of syngeneic CD4(+)CD25(-) T cells in RAG-deficient mice dramatically enhanced release of inflammatory cytokines and associated pathology upon endotoxin injection. Interferon (IFN)-gamma produced by T cells undergoing homeostatic proliferation was shown to be involved in the endotoxin hyperresponsiveness induced by CD4(+) T cell reconstitution. Co-transfer of CD4(+)CD25(+) nTreg with CD4(+)CD25(-) T cells inhibited the expansion of IFN-gamma-producing T cells and reduced endotoxin responses in RAG(-/-) mice. We conclude that (1) CD4(+) T cell reconstitution sensitizes lymphopenic hosts to endotoxin-induced pathology and (2) nTreg prevent this process by limiting the emergence of IFN-gamma-producing cells.
De Wilde
Virginie
V
Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
Benghiat
Fleur Samantha
FS
Novalrivas
Magali
M
Lebrun
Jean-François
JF
Kubjak
Carole
C
Oldenhove
Guillaume
G
Verdebout
Jean-Marc
JM
Goldman
Michel
M
Le Moine
Alain
A
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D004731:Endotoxins / Q000276:immunology*; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004731:Endotoxins; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D007371:Interferon-gamma