Type I Interferon Signaling in Dendritic Cells Stimulates the Development of Lymph-Node-Resident T Follicular Helper Cells

Cucak, Helena; Yrlid, Ulf; Reizis, Boris; Kalinke, Ulrich; Johansson‐Lindbom, Bengt

doi:10.1016/j.immuni.2009.07.005

Cited by 180 publications

(194 citation statements)

References 60 publications

(79 reference statements)

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“…On the other hand, in PP inj , 62.3 ± 3.6% of PD-1 hi CXCR5 hi T FH cells were FITC þ in accordance with previous reports showing most of the T FH cells to be retained in LNs ( Supplementary Fig. 5) 9,10,13 .…”

Section: Resultssupporting

confidence: 91%

“…In addition, T FH cells are generally regarded as LN-resident cells that stay in the LNs where they are induced. However, current information on residency of T FH cells is limited to LNs in immunized mice and mostly based on indirect evidence such as cell numbers observed under experimental blockade of egress 9,10 or expression levels of the egress-promoting sphingosine-1-phosphate receptor 1 (S1pr1) 11 . Whether residency in LNs is an exclusive feature of T FH cells or whether there are other LN-resident effector T cell subsets remains an open question.…”

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confidence: 99%

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Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure

et al. 2014

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Effector and memory CD4 þ T cells acquire distinct migratory properties depending on the type and location of the immune responses. Due to the highly dynamic nature of T cell circulation, the comprehensive analysis of these migratory routes requires dedicated experimental approaches. Here, we analyse the migration of effector/memory CD4 þ T cells by long-term in vivo cell tracking. We identify a resident population of antigen-experienced CD4 þ T cells that resides in lymph nodes and Peyer's patches without circulation or proliferation. Resident CD4 þ T cells constitute up to 50% of all effector/memory cells, including, but not limited to, follicular helper T cells. Furthermore, these non-circulating T cells possess a distinct T cell receptor repertoire and accumulate in Peyer's patches after continuous oral antigen exposure. Our results provide the first direct evidence for a resident population of effector/memory CD4 þ T cells that is retained in lymphoid tissues.

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Section: Resultssupporting

confidence: 91%

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confidence: 99%

Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure

et al. 2014

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“…Type I IFN signalling in DCs has previously been reported to be involved in the development of T FH cells in mice via the induction of IL-6 (ref. 35). We have previously shown that IL-6 expression is downregulated in response to TLR4 and fucose-specific DC-SIGN Here we found that IL-6 expression in response to LPS/LeX stimulation was independent of IFNR triggering or ISGF3 activation, as determined by blocking IFNR antibodies and IRF9 silencing, respectively ( Fig.…”

Section: Resultssupporting

confidence: 51%

“…35). Our data show that in human DCs, IL-6 is a prerequisite but not sufficient for T FH induction, while its induction via TLR4 is independent of IFNR triggering.…”

Section: Discussionmentioning

confidence: 65%

Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production

et al. 2014

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Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (T FH ) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKe, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3. Notably, ISGF3 induces expression of IL-27 subunit p28, and subsequent IL-27 secreted by DC-SIGN-primed DCs is pivotal for the induction of Bcl-6 þ CXCR5 þ PD-1 hi Foxp1 lo T FH cells, IL-21 secretion by T FH cells and T-cell-dependent IgG production by B cells. Thus, we have identified an essential role for DC-SIGN-induced ISGF3 by fucose-based PAMPs in driving IL-27 and subsequent T FH polarization, which might be harnessed for vaccination design.

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“…IFN-a facilitates the maturation of myeloid DC that contribute to T-cell activation and follicular T-helper cell differentiation [1], and that produce the B-cell survival factor B-cell activating factor (BAFF) [2]. IFN-a also directly stimulates CD4 T cells to enhance antigen-specific B-cell activation, increases TLR7 expression in B cells, and promotes T-independent B-cell proliferation and differentiation into early plasmablasts [3].…”

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confidence: 99%

Plasma cells in systemic lupus erythematosus: The long and short of it all

2011

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Plasma cells can be classified as long-or short-lived. The lifespan of a plasma cell largely depends on whether it arises from a germinal center or an extrafollicular locus and most importantly whether it can find a survival niche in the spleen or BM. In systemic lupus erythematosus (SLE) patients, long-lived plasma cells are believed to be responsible for the production of anti-RNA and anti-cardiolipin antibodies, whereas short-lived plasma cells, which are more susceptible to anti-proliferation therapies, are the main producers of anti-DNA antibodies. A previous study showed that transient overexpression of interferon-a (IFN-a), a cytokine that plays a pathogenic role in SLE, accelerates disease onset in lupusprone NZB/W mice. In this issue of the European Journal of Immunology, the same group report that IFN-a induces large numbers of short-lived plasma cells, accompanied by high titers of anti-dsDNA antibodies in NZB/W, but not BALB/c, mice. Our commentary discusses this interesting observation in the context of the previous data regarding plasma cell differentiation and conveys our view about the clinical implications with respect to therapies that target plasma cells in SLE patients.Keywords: Interferon-a . Plasma cells . Systemic lupus erythematosus See accompanying article by Mathian et al.Type I IFNs are believed to play a significant role in systemic lupus erythematosus (SLE) pathogenesis. IFN-a facilitates the maturation of myeloid DC that contribute to T-cell activation and follicular T-helper cell differentiation [1], and that produce the B-cell survival factor B-cell activating factor (BAFF) [2]. IFN-a also directly stimulates CD4 T cells to enhance antigen-specific B-cell activation, increases TLR7 expression in B cells, and promotes T-independent B-cell proliferation and differentiation into early plasmablasts [3]. In several lupus-prone mouse strains, type I IFNs accelerate the break in B-cell tolerance to nucleic acids that occurs spontaneously in these mice with age [4][5][6]. Nucleic acid-containing immune complexes, in turn, can activate intracellular TLRs, resulting in further release of type I IFNs and pro-inflammatory cytokines [7].Consistent with the known biologic functions of IFN-a, Mathian et al. [8] show in this issue of the European Journal of Immunology that NZB/W mice treated with a small dose of IFN-aexpressing adenovirus develop increased serum levels of BAFF, IL-6, and TNFa, and high titers of anti-dsDNA antibodies. In contrast, nonautoimmune BALB/c mice maintain tolerance to self-antigens despite IFN-a-induced upregulation of inflammatory mediators. This indicates that a genetic predisposition is required for IFN-a to initiate autoimmunity and may explain the reason why only few patients develop SLE during type I IFN therapy [3].The findings reported by Mathian et al. [8] complement the recent studies by our group, showing that IgG2a autoantibodies in IFN-a-induced NZB/W mice were derived from germinal centers, whereas IgG3 autoantibodies were derived predominantly from extra...

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Type I Interferon Signaling in Dendritic Cells Stimulates the Development of Lymph-Node-Resident T Follicular Helper Cells

Cited by 180 publications

References 60 publications

Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure

Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure

Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production

Plasma cells in systemic lupus erythematosus: The long and short of it all

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