BDC12-4.1 T-cell receptor transgenic insulin-specific CD4 T cells are resistant to in vitro differentiation into functional Foxp3+ T regulatory cells.
The infusion of ex vivo-expanded autologous T regulatory (Treg) cells is potentially an effective immunotherapeutic strategy against graft-versus-host disease (GvHD) and several autoimmune diseases, such as type 1 diabetes (T1D). However, in vitro differentiation of antigen-specific T cells into functional and stable Treg (iTreg) cells has proved challenging. As insulin is the major autoantigen leading to T1D, we tested the capacity of insulin-specific T-cell receptor (TCR) transgenic CD4(+) T cells of the BDC12-4.1 clone to convert into Foxp3(+) iTreg cells. We found that in vitro polarization toward Foxp3(+) iTreg was effective with a majority (>70%) of expanded cells expressing Foxp3. However, adoptive transfer of Foxp3(+) BDC12-4.1 cells did not prevent diabetes onset in immunocompetent NOD mice. Thus, in vitro polarization of insulin-specific BDC12-4.1 TCR transgenic CD4(+) T cells toward Foxp3+ cells did not provide dominant tolerance in recipient mice. These results highlight the disconnect between an in vitro acquired Foxp3(+) cell phenotype and its associated in vivo regulatory potential.
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Ghanashyam
G
Sarikonda
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Georgia
G
Fousteri
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Sowbarnika
S
Sachithanantham
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Jacqueline F
JF
Miller
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Amy
A
Dave
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Therese
T
Juntti
Type 1 Diabetes R&D center, Novo Nordisk Inc., Seattle, Washington, USA.
Ken T
KT
Coppieters
Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA; Type 1 Diabetes R&D center, Novo Nordisk Inc., Seattle, Washington, USA.
Matthias
M
von Herrath
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007328:Insulin / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D011948:Receptors, Antigen, T-Cell