title: Host-derived CD4+ T cells attenuate stem cell-mediated transfer of autoimmune arthritis in lethally irradiated C57BL/6.g7 mice.
abstract: OBJECTIVE
  In the K/BxN mouse model of inflammatory arthritis, T cells carrying a transgenic T cell receptor initiate disease by helping B cells to produce arthritogenic anti-glucose-6-phosphate isomerase (anti-GPI) autoantibodies. We found that lethally- irradiated lymphocyte-deficient C57BL/6 (B6).g7 (I-A(g7) +) recombinase-activating gene-deficient (Rag(-/-)) mice reconstituted with K/BxN hematopoietic stem and progenitor cells exhibit arthritis by week 4. In contrast, healthy B6.g7 recipients of K/BxN hematopoietic stem and progenitor cells show only mild arthritis, with limited extent and duration. The objective of this study was to investigate the factors responsible for the attenuation of arthritis in B6.g7 recipients.
  
  
  METHODS
  Antibody responses were measured by enzyme-linked immunosorbent assay. Fluorescence-activated cell sorting analyses were performed for testing chimerism, expression of markers of activation and suppression, tetramer binding, and intracellular cytokines in CD4+ T cells. Suppressive activity of CD4+ T cells was studied by adoptive transfer.
  
  
  RESULTS
  Titers of anti-GPI antibodies in reconstituted B6.g7 mice were ∼60-fold lower than in reconstituted B6.g7 Rag(-/-) mice. Examination of chimerism in the reconstituted B6.g7 mice showed that B cells and myeloid cells in these mice were donor derived, but CD4+ T cells were primarily host derived and enriched for cells expressing the conventional regulatory markers CD25 and FoxP3. Notably, CD4+CD25-FoxP3- T cells expressed markers of suppressive function (CD73 and folate receptor 4), and delayed disease after adoptive transfer. Activation of donor-derived CD4+ T cells was reduced, and thymic deletion of these cells appeared increased.
  
  
  CONCLUSIONS
  Despite myeloablation, host CD4+ T cells having a regulatory phenotype emerge in these mice and attenuate autoimmunity.
authors.affiliation: Stanford University School of Medicine, Stanford, California 94305-5164, USA.
authors.forename: Narendiran
authors.initials: N
authors.lastname: Rajasekaran
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Phi
authors.initials: P
authors.lastname: Truong
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rinderknecht
authors.forename: Claudia
authors.initials: C
authors.lastname: Macaubas
authors.forename: Georg F
authors.initials: GF
authors.lastname: Beilhack
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D007156:Immunologic Memory / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D011956:Receptors, Cell Surface; C543634:folate receptor 4, mouse; C064658:RAG-1 protein; D015720:5'-Nucleotidase; D005956:Glucose-6-Phosphate Isomerase