title: Adoptive transfer of DNT cells induces long-term cardiac allograft survival and augments recipient CD4(+)Foxp3(+) Treg cell accumulation.
abstract: Regulatory T (Treg) cells play an important role in the regulation of immune responses but whether Treg will induce tolerance in transplant recipients in the clinic remains unknown. Our previous studies have shown that TCRαβ(+)CD3(+)CD4⁻CD8⁻NK1.1⁻ (double negative, DN) T cells suppress T cell responses and prolong allograft survival in a single locus MHC-mismatched mouse model. In this study, we investigated the role of DNT cells in a more robust, fully MHC-mismatched BALB/c to C57BL/6 transplantation model, which may be more clinically relevant. Adoptive transfer of DNT cells in combination with short-term rapamycin treatment (days 1-9) induced long-term heart allograft survival (101±31 vs. 39±13 days rapamycin alone, p<0.01). Furthermore adoptive transfer DNT cells augmented CD4+Foxp3+ Treg cells accumulation in transplant recipients while depletion of CD4(+) Treg cells by anti-CD25 inhibited the effect of DNT cells on long-term graft survival (48±12 days vs. 101±31 days, p<0.001). In conclusion, DNT cells combined with short-term immunosuppression can prolong allograft survival, which may be through the accumulation of CD4(+)Foxp3(+) Treg cells in the recipient. Our result suggests that allograft tolerance may require the co-existence of different type Treg cell phenotypes which are affected by current immunosuppression.
authors.affiliation: The Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada. zhuxu.zhang@lhsc.on.ca
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.forename: Dameng
authors.initials: D
authors.lastname: Lian
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Hongtao
authors.initials: H
authors.lastname: Sun
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors; D006085:Graft Survival; D016027:Heart Transplantation; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D020123:Sirolimus