Pancreatic islets induce CD4(+) [corrected] CD25(-)Foxp3(+) [corrected] T-cell regulated tolerance to HY-mismatched skin grafts.
BACKGROUND
The ability to induce and maintain antigen-specific immunologic tolerance is the ultimate goal in allo-transplantation. Here, we report that the transplantation of unmanipulated murine pancreatic islets across the HY disparity induced transplantation tolerance that prevented HY-mismatched skin grafts being rejected.


METHODS
Three hundred islet equivalent of freshly isolated islets from male C57BL/6 donor mice was transplanted underneath the kidney capsule of syngeneic female recipients rendered diabetic by streptozotocin. Nephrectomy was carried out to remove the islet graft and retransplantation was performed using the contralateral kidney. For skin transplantation, donor tail skin was transplanted onto the lateral thorax.


RESULTS
Islets from male C57BL/6 donors transplanted to syngeneic female recipients cured diabetes and the mice survived indefinitely. The acceptance of second grafts and rejection of third party islet grafts indicated antigen-specific transplantation tolerance. However, flow cytometry and ELISPOT analysis demonstrated that the HY-specific T cells were not deleted or anergized. A 2-fold increase of CD4+Foxp3+ regulatory T cells (Tregs) was observed in spleen and lymph nodes. Notably, CD25- Tregs increased threefold over levels in naïve mice. Adoptive transfer of CD4+ T cells to neonatal mice could transfer tolerance. At the graft site in long-term tolerant mice, CD4+ T cells, 40% of which were CD4+Foxp3+ Tregs (43% CD25-, 57% CD25+) infiltrated the peri-islet spaces.


CONCLUSIONS
Unmanipulated pancreatic islets can induce immunologic tolerance associated with peripherally induced CD4+Foxp3+ Tregs, a significant proportion of which notably are CD25-.
Yoon
Il-Hee
IH
Department of Microbiology and Immunology, Seoul National University Hospital, Seoul, South Korea.
Choi
Seung-Eun
SE
Kim
Yong-Hee
YH
Yang
Seung-Ha
SH
Park
Ji-Hyun
JH
Park
Chan-Sik
CS
Kim
Youngji
Y
Kim
Jung-Sik
JS
Kim
Sang-Joon
SJ
Simpson
Elizabeth
E
Park
Chung-Gyu
CG
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D006182:H-Y Antigen / Q000276:immunology*; D006650:Histocompatibility Testing / Q000379:methods; D007108:Immune Tolerance / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D013370:Subrenal Capsule Assay; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology; D014185:Transplantation, Isogeneic
D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006182:H-Y Antigen; D053645:Interleukin-2 Receptor alpha Subunit