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?? T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

ABSTRACT: Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of ?? T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that ?? T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although ?? T cells produced Th17 cell-associated cytokines in response to IL-23, their major function was to prevent the development of regulatory T (Treg) cell responses. IL-23-activated ?? T cells rendered ?? effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cells into Foxp3(+) Treg cells in vivo. Thus, IL-23, which by itself has no direct effect on Treg cells, is able to disarm Treg cell responses and promote antigen-specific effector T cell responses via activating ?? T cells.

SUBMITTER: Petermann F

PROVIDER: S-EPMC3008772 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

Petermann Franziska F Rothhammer Veit V Claussen Malte C MC Haas Jan D JD Blanco Lorena Riol LR Heink Sylvia S Prinz Immo I Hemmer Bernhard B Kuchroo Vijay K VK Oukka Mohamed M Korn Thomas T

Immunity 20100909 3

Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of γδ T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that γδ T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although γδ T cells produced Th17 cell-associated cytokines in response to IL-23, their major function was to prevent t ...[more]

PMID: 20832339

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Project description:BackgroundThe systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs.Methodology/principal findingsTo achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation.Conclusion/significanceThe study described herein, identifies the first member of the TGF beta/BMP family of stem cell regulators as a novel tolerogenic factor released by NPCs. Full exploitation of this pathway as an efficient tool for vaccination therapy in autoimmune inflammatory conditions is underway.

Dataset Information

?? T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

Publications

γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

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