title: Alternatively Activated Macrophages Boost Induced Regulatory T and Th17 Cell Responses during Immunotherapy for Colitis.
abstract: Induced regulatory T (iTreg) and Th17 cells promote mucosal homeostasis. We used a T cell transfer model of colitis to compare the capacity of iTreg and Th17 cells to develop in situ following the transfer of naive CD4(+)CD45RB(hi)T cells intoRag1(-/-)C57BL/6 or BALB/c mice, the prototypical Th1/M1- and Th2/M2-prone strains. We found that the frequency and number of Foxp3(+)iTreg cells and Th17 cells were significantly reduced in C57BL/6 mice compared with the BALB/c strain. C57BL/6 mice with colitis were also resistant to natural Treg cell immunotherapy. Pretreatment of C57BL/6Rag1(-/-)mice with IL-4 plus IL-13, or with M2a but not M1 macrophages, dramatically increased the generation of iTreg and Th17 cells. Importantly, M2a transfers, either as a pretreatment or in mice with established colitis, allowed successful immunotherapy with natural Treg cells. M2a macrophages also reduced the generation of pathogenic iTreg cells that lost Foxp3 expression, suggesting that they stabilize the expression of Foxp3. Thus, polarized M2a macrophages drive a directionally concordant expansion of the iTreg-Th17 cell axis and can be exploited as a therapeutic adjuvant in cell-transfer immunotherapy to re-establish mucosal tolerance.
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Dipica
authors.initials: D
authors.lastname: Haribhai
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ziegelbauer
authors.affiliation: Section of Endocrinology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Shuang
authors.initials: S
authors.lastname: Jia
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Kyle
authors.initials: K
authors.lastname: Upchurch
authors.affiliation: Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Ke
authors.initials: K
authors.lastname: Yan
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Erica G
authors.initials: EG
authors.lastname: Schmitt
authors.affiliation: Section of Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and.
authors.forename: Nita H
authors.initials: NH
authors.lastname: Salzman
authors.affiliation: Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Pippa
authors.initials: P
authors.lastname: Simpson
authors.affiliation: Section of Endocrinology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hessner
authors.affiliation: Division of Immunology, Children's Hospital Boston, Boston, MA 02115.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
authors.affiliation: Section of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; cwilliam@mcw.edu.
authors.forename: Calvin B
authors.initials: CB
authors.lastname: Williams
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000628:therapy*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018793:Interleukin-13 / Q000627:therapeutic use; D015847:Interleukin-4 / Q000627:therapeutic use; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018793:Interleukin-13; D015847:Interleukin-4