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.
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Menghua
M
Zeng
Elisabeth
E
Guinet
Mahyar
M
Nouri-Shirazi
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