Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses

Nasreen, Mariam, Waldie, Tanya M., Dixon, Chantelle M. and Steptoe, Raymond J. (2010) Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses. European Journal of Immunology, 40 7: 2016-2025. doi:10.1002/eji.200940085


Author Nasreen, Mariam
Waldie, Tanya M.
Dixon, Chantelle M.
Steptoe, Raymond J.
Title Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses
Formatted title
Steady-state antigen-expressing dendritic cells terminate CD4+ memory T-cell responses
Journal name European Journal of Immunology   Check publisher's open access policy
ISSN 0014-2980
1521-4141
Publication date 2010-07-01
Sub-type Article (original research)
DOI 10.1002/eji.200940085
Open Access Status DOI
Volume 40
Issue 7
Start page 2016
End page 2025
Total pages 10
Editor Foo Yoo Liew
Place of publication Weinheim, Germany
Publisher Wiley-VCH
Language eng
Abstract Dendritic cells (DC) initiate the differentiation of CD4(+) helper T cells into effector cells including Th1 and Th17 responses that play an important role in inflammation and autoimmune disease pathogenesis. In mice, Th1 and Th17 responses are regulated by different conventional (c) DC subsets, with cDC1 being the main producers of IL-12p70 and inducers of Th1 responses, while cDC2 produce IL-23 to promote Th17 responses. The role that human DC subsets play in memory CD4(+) T cell activation is not known. This study investigated production of Th1 promoting cytokine IL-12p70, and Th17 promoting cytokines, IL-1β, IL-6, and IL-23, by human blood monocytes, CD1c(+) DC, CD141(+) DC, and plasmacytoid DC and examined their ability to induce Th1 and Th17 responses in memory CD4(+) T cells. Human CD1c(+) DC produced IL-12p70, IL-1β, IL-6, and IL-23 in response to R848 combined with LPS or poly I:C. CD141(+) DC were also capable of producing IL-12p70 and IL-23 but were not as proficient as CD1c(+) DC. Activated CD1c(+) DC were endowed with the capacity to promote both Th1 and Th17 effector function in memory CD4(+) T cells, characterized by high production of interferon-γ, IL-17A, IL-17F, IL-21, and IL-22. These findings support a role for CD1c(+) DC in autoimmune inflammation where Th1/Th17 responses play an important role in disease pathogenesis.
Formatted abstract
CD4+ T cells are important effectors of inflammation and tissue destruction in many diseases of immune dysregulation. As memory T cells develop early during the preclinical stages of autoimmune and inflammatory diseases, immunotherapeutic approaches to treatment of these diseases, once established, must include the means to terminate memory T-cell responses. Traditionally, it has been considered that, due to their terminally differentiated nature, memory T cells are resistant to tolerance induction, although emerging evidence indicates that some immunotherapeutic approaches can terminate memory T-cell responses. Here, we demonstrate that CD4+ memory T-cell responses can be terminated when cognate antigen is transgenically expressed in steady-state DC. Transfer of in-vitro-generated CD4+ memory T cells establishes, in nontransgenic recipients, a stable and readily recalled memory response to cognate antigen. In contrast, upon transfer to mice expressing cognate antigen targeted to DC, memory CD4+ T cells undergo a phase of limited proliferation followed by substantial deletion, and recall responses are effectively silenced. This finding is important in understanding how to effectively apply immunotherapy to ongoing T-cell-mediated autoimmune and inflammatory diseases.
Keyword CD4(+) T cells
DC
Tolerance
Parenchymal self-antigen
In-vivo
Peripheral tolerance
Cross-presentation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 20 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 08 Aug 2010, 10:06:14 EST