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Alternatively Activated Macrophages Boost Induced Regulatory T and Th17 Cell Responses during Immunotherapy for Colitis. J Immunol 2016 Apr 15;196(8):3305-17

Date

03/02/2016

Pubmed ID

26927797

Pubmed Central ID

PMC4851766

DOI

10.4049/jimmunol.1501956

Scopus ID

2-s2.0-84974839190 (requires institutional sign-in at Scopus site)   39 Citations

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.

Author List

Haribhai D, Ziegelbauer J, Jia S, Upchurch K, Yan K, Schmitt EG, Salzman NH, Simpson P, Hessner MJ, Chatila TA, Williams CB

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Director, Professor in the Pediatrics department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ke Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Colitis
Forkhead Transcription Factors
Immune Tolerance
Immunotherapy, Adoptive
Interleukin-13
Interleukin-4
Macrophage Activation
Macrophages
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes, Regulatory
Th17 Cells