Analysis of adhesion molecules, target cells, and role of IL-2 in human FOXP3+ regulatory T cell suppressor function.
FOXP3(+) regulatory T cells (Tregs) are central to the maintenance of self-tolerance and immune homeostasis. The mechanisms of action and cellular targets for Treg-mediated suppression remain controversial. The critical adhesion molecules utilized by Tregs for the interaction with their target cells have not been well characterized. We show that human CD4(+)FOXP3(+)CD25(high) cells (hTregs) suppress the activation of mouse responders as efficiently as mouse Tregs. LFA-1 (CD11a/CD18) on the hTregs is critical for their suppressor function, since suppression can be reversed with blocking anti-hCD11a or anti-hCD18 mAb. Tregs from patients with LFA-1 deficiency fail to suppress human and mouse responders. Mouse CD4(+) T cells deficient in ICAM-1 can be suppressed by hTregs, indicating that the hTregs target mouse dendritic cells (DCs) through the binding of human LFA-1 to mouse ICAM-1. Coculture of mouse DCs with hTregs, but not hTregs from LFA-1-deficient patients, prevented the up-regulation of CD80/CD86 on the DCs and their capacity to activate responder T cells. Lastly, IL-2 is not required for hTreg suppressor function under optimal stimulatory condition and IL-2 consumption plays no role in hTreg-mediated suppression. Taken together, one of the mechanisms of Treg-mediated suppression functions across species and mediates an LFA-1/ICAM-1-dependent interaction between Tregs and DCs.
Tran
Dat Q
DQ
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Glass
Deborah D
DD
Uzel
Gulbu
G
Darnell
Dirk A
DA
Spalding
Christine
C
Holland
Steven M
SM
Shevach
Ethan M
EM
D000328:Adult; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D007165:Immunosuppression Therapy; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1