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CD4+CD25+FoxP3+ T Regulatory Cells Play a Critical Role in Tolerance to Pancreatic Islets Engineered to Display on Their Surface an Exogenous FasL Protein
Author(s) -
Yolcu Esma S.,
Zhao Hong,
BanduraMorgan Laura,
Lacelle Chantale,
Askenasy Nadir,
Shirwan Haval
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.862.15
Subject(s) - foxp3 , immune tolerance , il 2 receptor , transplantation , clonal deletion , immunology , islet , microbiology and biotechnology , antigen , medicine , biology , t cell , immune system , cancer research , t cell receptor , endocrinology , diabetes mellitus
Objective: We have shown that islets engineered to display on their surface a chimeric form of FasL with streptavidin (SA‐FasL) induce robust localized tolerance when transplanted into allogeneic recipients. The objective of this study was to elucidate mechanisms of tolerance in this model. Methods: RIP‐OVA BALB/c islets were engineered by cell surface modification with biotin followed by the display of chimeric SA‐FasL. SA‐FasL‐engineered islets were transplanted into streptozotocin diabetic C57BL/6 mice under transient cover of rapamycin. Graft recipients were adoptively transferred with OT‐I TCR transgenic T cells and analyzed for donor‐specific proliferation, clonal deletion, and increased frequencies of T regulatory cells (Treg). Results: Long‐term recipients generated a normal proliferative and cytokine response to donor antigens, demonstrating lack of systemic tolerance. Graft acceptance involved clonal deletion of alloreactive T cells within the kidney draining lymph nodes early post‐transplantation. Although analysis of CD4+CD25+FoxP3+ Treg cells did not revealed their increased frequency in the periphery as compared with rejecting controls, in vivo depletion of Treg cells using an antibody to CD25 early or late post‐transplantation resulted in prompt rejection of tolerated grafts. Conclusion: Tolerance to SA‐FasL‐engineered islets is localized to the graft and involves clonal deletion of alloreactive T cells early post‐transplantation followed by generation/induction of Treg cells that maintain tolerance. NIH (R21 DK61333, R01 AI47864, R21 AI057903 , R21 HL080108 ), JDRF (1‐2001‐328), and ADA (1‐05‐JF‐56).