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Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2
Journal article   Open access   Peer reviewed

Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2

Katarina Kulhankova, Todd Rouse, Mohamed E Nasr and Elizabeth H Field
PloS one, Vol.7(9), pp.e43609-e43609
2012
DOI: 10.1371/journal.pone.0043609
PMCID: PMC3440416
PMID: 22984435
url
https://doi.org/10.1371/journal.pone.0043609View
Published (Version of record) Open Access

Abstract

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) restrict inflammatory responses to self and nonself. Aberrant Treg activity is pathologic: Insufficient Treg activity is implicated in autoimmunity, allergy, and graft-versus-host-disease; overabundant activity is implicated in chronic infection and cancer. Tregs require IL-2 for their expansion and acquisition/execution of suppressor function; however, because Tregs cannot produce IL-2, they depend on IL-2 from an exogenous source. Until now, that IL-2 source had not been established. We asked whether dendritic cells (DCs) could supply IL-2 to Tregs and, if so, what was required for that delivery. We used flow cytometry, IL-2 ELISPOT, RT-qPCR, and IL-2 promoter-driven reporter assays to measure intracytoplasmic IL-2, secreted protein, IL-2 message and IL-2 promoter activity in bone marrow-derived (BMDC) and splenic DCs. We examined conjugate formation between Tregs, conventional CD4(+) cells, and IL-2-expressing DCs. We measured Treg levels of CD25, Foxp3, and suppressor function after co-culture with IL-2 sufficient and IL-2(-/-) DCs. We generated IL-2-mCherry-expressing DCs and used epifluorescence microscopy and flow cytometry to track IL-2 transfer to Tregs and test requirements for transfer. Between 0.7 to 2.4% of DCs constitutively produced IL-2 and diverted IL-2 secretion to Tregs by preferentially forming conjugates with them. Uptake of DC IL-2 by Tregs required cell-cell contact and CD25. Tregs increased levels of CD25 and Foxp3 from baseline and showed greater suppressor function when co-cultured with IL-2-sufficient DCs, but not when co-cultured with IL-2(-/-) DCs. Exogenous IL-2, added in excess of 500 U/ml to co-cultures with IL-2(-/-) DCs, restored Treg suppressor function. These data support a model of juxtacrine delivery of IL-2 from DCs to Tregs and suggest that a subset of DCs modulates Treg function through controlled, spatial delivery of IL-2. Knowledge of how DCs regulate Tregs should be integrated into the design of interventions intended to alter Treg function.
 Interleukin-2 - metabolism Cell Proliferation Dendritic Cells - immunology Mice, Inbred C57BL Cell Communication Lymphocyte Culture Test, Mixed T-Lymphocytes, Regulatory - immunology Interleukin-2 - genetics Phenotype Animals Interleukin-2 Receptor alpha Subunit - metabolism Forkhead Transcription Factors - metabolism T-Lymphocytes, Regulatory - cytology Transcription, Genetic Dendritic Cells - cytology Mice Mice, Inbred BALB C CD4 Antigens - metabolism

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