B7-1 and B7-2 differentially control peripheral homeostasis of CD4(+)CD25(+)Foxp3(+) regulatory T cells.
Targeting the CD28/B7 interaction remains among the most promising approaches to treat transplant rejection. A drawback to this approach is however the observations of decreased numbers of naturally occurring regulatory T cells (Tregs) in CD28(-) or B7-deficient non-obese diabetic (NOD) mice, cells that maintain immunological self tolerance, prevent autoimmunity and control immune responses to transplants. In this study, therefore, we investigated the relative contributions of B7-1 and B7-2, the only known ligands of CD28, on the thymic development and peripheral homeostasis of Tregs. Our data indicates that the absence of both B7-1 and B7-2 result in a dramatic reduction in the frequencies of Tregs in thymus and peripheral tissues of B7-1/B7-2-deficient mice with no apparent changes in the percentage and distribution of conventional T-cell subsets. In addition, neither B7-1 nor B7-2 expression alone is sufficient for the development and peripheral homeostasis of Tregs. Interestingly, while B7-1 and B7-2 equally contribute to thymic development of Tregs, the significant loss in peripheral homeostasis of Tregs is more evident in the absence of B7-2 as compared to B7-1. Consistent with these results we found that B7-2-deficient DCs are less effective than B7-1-deficient DCs in maintaining Tregs in vitro due to their inability to induce IL-2 production by conventional T cells and sustain Tregs expression of CD25. This study provides the first demonstration of relative roles of B7-1 and B7-2 in Tregs homeostasis and suggests that therapeutic approaches designed to selectively interrupt CD28/B7-2 interaction could indeed have measurable impact on sustaining Tregs homeostasis.
Zeng
Menghua
M
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Guinet
Elisabeth
E
Nouri-Shirazi
Mahyar
M
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit