Premium
Expansion of CD4+ regulatory T cells by BMDC in the absence of exogenous IL‐2 and TGFβ is determined by the strength of the TCR signal
Author(s) -
Turner Michael Stuart,
Morel Penelope A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1073.6
Subject(s) - foxp3 , t cell receptor , nod , effector , biology , microbiology and biotechnology , chemistry , immunology , t cell , immune system , endocrinology , diabetes mellitus
Our group has previously reported that onset of Type 1 diabetes could be delayed in NOD mice by administration of BMDC grown with GM‐CSF & IL‐4 (G4DC) and enriched for high‐exfpression of MHC II and co‐stimulatory molecules, whereas DC grown with only GM‐CSF (GMDC) were not therapeutically effective. By studying the interaction of tolerogenic G4DC with CD4 + T cells from BDC2.5 TCR Tg mice, we have found that G4DC can induce proliferation of both Foxp3 + (Treg) and Foxp3 − (Th) CD4 + T cells, in the absence of exogenous IL‐2 or TGFβ. In these experiments CFSE‐labeled BDC2.5 CD4 + T cells were cultured with G4DC, pulsed with increasing doses of high‐ and low‐affinity peptide mimetopes. The presence of Treg in proliferating in and non‐proliferating T cells was assessed after 7 days by ICC for FoxP3. We observed a significant expansion of FoxP3 + Treg when low doses of specific peptides were used, whereas high peptide doses induced expansion of effector T cells. This phenomenon is not unique to self‐reactive T cells since similar results were obtained in the OVA‐specific DO11.10 TCR Tg system. Interestingly, G4DC also induced expansion of Tregs from nontransgenic NOD CD4 + T cells, whether or not the DCs were peptide‐pulsed, suggesting that G4DC from NOD mice may present low levels of endogenous self‐antigen. These data suggest that therapeutic G4DC function, in part, by inducing Treg expansion and that, in the absence of exogenous TGF‐β, the strength of the TCR signal is critical for Treg expansion/induction. Funded by the American Diabetes Association (PM).