title: Induction of self-antigen-specific Foxp3+ regulatory T cells in the periphery by lymphodepletion treatment with anti-mouse thymocyte globulin in mice.
abstract: Lymphodepletion therapies are increasingly tested for controlling immune damage. One appealing premise for such a therapy is that it may 'reboot' the immune system and restore immune tolerance. However, the tolerogenic potential of lymphodepletion therapies remains controversial. The debate is exemplified by conflicting evidence from the studies of anti-thymocyte globulin (ATG), a prototype of immunodepleting drugs, in particular on whether it induces CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells. To understand the impact of ATG on T cells at a clonal level in vivo, we studied the effect of anti-mouse thymocyte globulin (mATG) in a reductionist model in which the T-lymphocyte repertoire consists of a single clone of pathogenic T effector (Teff) cells specific to a physiological self-antigen. The mATG treatment led to peripheral induction of antigen-specific Treg cells from an otherwise monoclonal Teff repertoire, independent of thymic involvement. The de novo induction of Treg cells occurred consistently in local draining lymph nodes, and persistence of induced Treg cells in blood correlated with long-term protection from autoimmune destruction. This study provides in vivo evidence for clonal conversion from a pathogenic self-antigen-specific Teff cell to a Treg cell in the setting of immunodepletion therapies.
authors.affiliation: Department of Microbiology and Immunology Diabetes Research Institute Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Maria
authors.initials: M
authors.lastname: Guillioli
authors.forename: Oliver
authors.initials: O
authors.lastname: Umland
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Chen
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000494:pharmacology* / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D060908:CTLA-4 Antigen; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D039001:Integrin alpha Chains / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012727:Sex Characteristics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000961:Antilymphocyte Serum; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D039001:Integrin alpha Chains; D053645:Interleukin-2 Receptor alpha Subunit; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D011948:Receptors, Antigen, T-Cell; C091367:alpha E integrins