Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro.
Regulatory T cells (Treg) play important roles in suppressing immune responses and maintaining tolerance. Rabbit antithymocyte globulin (rATG) and horse ATG (hATG) are widely used in the treatment of immune-mediated syndromes, but their effects on Treg are unknown. We show here that in vitro culture of normal human peripheral blood mononuclear cells (PBMCs) with a low-dose rATG resulted in marked expansion of functional Treg by converting CD4+CD25- T cells to CD4+CD25+ T cells. hATG did not expand but rather decreased Treg. Immuno-blot showed increased expression of FOXP3 and NFAT1 in CD4+CD25- and CD4+CD25+ T cells exposed to rATG. PBMCs treated with rATG displayed increased interleukin-10 in culture supernatants than those treated with hATG. Furthermore, rATG and hATG showed differences in their potential to stimulate CD4+ T cells as examined using different activation markers. Microarray revealed that rATG induced markedly different gene-expression patterns in PBMCs, compared with hATG-treated or untreated PBMCs. Our findings indicate that rATG expanded Treg, probably through transcriptional regulation by enhanced NFAT1 expression, in turn conferring CD4+CD25- T cell FOXP3 expression and regulatory activity. The therapeutic effects of rATG may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function.
Feng
Xingmin
X
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. fengx2@nhlbi.nih.gov
Kajigaya
Sachiko
S
Solomou
Elena E
EE
Keyvanfar
Keyvan
K
Xu
Xiuli
X
Raghavachari
Nalini
N
Munson
Peter J
PJ
Herndon
Thomas M
TM
Chen
Jichun
J
Young
Neal S
NS
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006736:Horses; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011817:Rabbits; D013045:Species Specificity; D013577:Syndrome; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D000961:Antilymphocyte Serum; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D016753:Interleukin-10