In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness.
Regulatory T cells (Tregs) hold much promise for the therapy of allergy and autoimmunity, but their use is hampered by lack of Ag specificity (natural Tregs) and difficulty to expand in vitro or in vivo (adaptive Tregs). We designed a method for in vivo induction of Ag-specific Tregs, in BALB/c H-2d, that share characteristics with type 1 Tregs (Tr1). A retroviral vector was constructed encoding a major T cell epitope of a common allergen, Der p 2, fused to an endosomal targeting sequence (gp75) for efficient MHC class II presentation. B cells transduced with such construct were adoptively transferred to BALB/c mice before or after peptide immunization. Long-lasting Ag-specific immune tolerance was achieved in both cases. Genetically modified B cells constitutively expressed the transgene for at least 3 mo. B cells from IL-10(-/-) mice were unable to induce tolerance. Upon transfer, B cells induced Foxp3(-)CD4(+) T cells showing phenotypic and functional characteristics comparable to Tr1-cells, including production of IL-10 but not of TGF-beta, and high expression of CTLA-4. Adoptive transfer of such T cells conferred unresponsiveness to allergen immunization and prevented the development of Der p 2-induced asthma. Functional Tr1-like cells can therefore be induced in vivo using retrovirally transduced B cells.
Ahangarani
Roxana Roohi
RR
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Janssens
Wim
W
VanderElst
Luc
L
Carlier
Vincent
V
VandenDriessche
Thierry
T
Chuah
Marinee
M
Weynand
Birgit
B
Vanoirbeek
Jeroen A J
JA
Jacquemin
Marc
M
Saint-Remy
Jean-Marie
JM
D019264:Adoptive Transfer / Q000379:methods; D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000235:genetics*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014161:Transduction, Genetic / Q000379:methods
D018984:Epitopes, T-Lymphocyte; D016753:Interleukin-10