Redirection of regulatory T cells with predetermined specificity for the treatment of experimental colitis in mice.
OBJECTIVE
Treatment with ex vivo expanded regulatory T cells (Tregs) is regarded as a promising therapeutic approach in inflammatory bowel disease but is hampered by impaired Treg accumulation and function at inflammatory sites. We aim to study whether antigen-specific redirected Tregs can overcome these limitations.


METHODS
We developed transgenic mice whose T cells, including Tregs, express chimeric receptor (CR) made of antibody variable region as recognition unit and T-cell stimulatory and costimulatory domains to activate specifically in response to the predetermined model antigen 2,4,6-trinitrophenol (TNP).


RESULTS
TNP-specific CR-bearing Tregs were potently and specifically activated by exogenous TNP and suppressed effector T cells in the absence of costimulatory B7-CD28 interaction. TNP-specific transgenic (Tg) mice were resistant to 2,4,6-trinitrobenzene sulphonic acid (TNBS) colitis but not to other hapten-mediated colitis. Adoptive transfer of CR-bearing Tregs to wild-type mice with TNBS colitis was associated with significant amelioration of colitis and improved survival. Although TNP-specific CR-bearing Tregs did not suppress oxazolone colitis, they cured it after addition of traces of TNBS to oxazolone-inflamed colons, demonstrating a "bystander" effect. In vivo imaging of adoptively transferred CR-bearing Tregs demonstrated that they preferentially migrate to TNBS-induced colonic mucosal lesions within hours of induction of colitis.


CONCLUSIONS
Tregs can be redirected with specificity distinct from that of pathogenic lymphocytes, accumulate at colonic inflammatory lesions, and suppress effector T cells in a specific, nonmajor histocompatibility complex-restricted, and noncostimulatory-dependent manner, resulting in significant amelioration of colitis. Hopefully, this approach will lead to a novel therapy for inflammatory bowel disease, as well as other inflammatory diseases.
Elinav
Eran
E
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Waks
Tova
T
Eshhar
Zelig
Z
D000818:Animals; D024201:Bystander Effect; D018106:CD28 Antigens / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D003106:Colon / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000276:immunology; D018928:Immunity, Mucosal; D007135:Immunoglobulin Variable Region / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007413:Intestinal Mucosa / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010081:Oxazolone; D010851:Picrates / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
D018106:CD28 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006649:Histocompatibility Antigens; D007135:Immunoglobulin Variable Region; D010851:Picrates; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D010081:Oxazolone; D014302:Trinitrobenzenesulfonic Acid; C005858:picric acid