CD69 Regulates Type I IFN-Induced Tolerogenic Signals to Mucosal CD4 T Cells That Attenuate Their Colitogenic Potential

Radulovic, Katarina; Manta, Calin; Rossini, Valerio; Holzmann, Karlheinz; Kestler, Hans A.; Wegenka, Ursula; Nakayama, Toshinori; Niess, Jan Hendrik

doi:10.4049/jimmunol.1100765

Cited by 72 publications

(93 citation statements)

References 56 publications

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“…The role of CD69 as a negative regulator of the immune system has remained a controversial issue during the last years (23). However, very recent studies by independent groups show that CD69 plays a crucial role in the suppressor function of mouse and human Treg cells as well as in the generation of in vitro-induced Treg cells (12,16,(24)(25)(26). Nevertheless, the specific role of the C-type lectin in the development of Treg cells in the thymus remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, two different genetic approaches in mice and a recent study in humans indicate that CD69 expression in pTreg cells is required to maintain immunological tolerance. CD69 deficiency in mice compromises T cell-induced colitis and the establishment of oral tolerance after antigen challenge in vivo (24), and CD69 ϩ pTreg cells are essential for the prevention of asthmatic reactions to harmless antigens (12). Furthermore, a subset of CD69 ϩ Treg cells in the blood of healthy human donors seems to have a relevant immune-regulatory role (25).…”

Section: Discussionmentioning

confidence: 99%

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Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

Sánchez-Díaz

Blanco-Domínguez

Lasarte

et al. 2017

Molecular and Cellular Biology

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Thymus-derived regulatory T (tTreg) cells are key to preventing autoimmune diseases, but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg cell homeostasis through the regulation of BIC/microRNA 155 (miR-155) and its target, suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69 ϩ/Ϫ or Foxp3-mRFP/cd69 Ϫ/Ϫ reporter mice and short hairpin RNA (shRNA)-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3 ϩ cells. This results in BIC/miR-155 inhibition, increased SOCS-1 expression, and severely impaired tTreg cell development in embryos, adults, and Rag2 Ϫ/Ϫ ␥c Ϫ/Ϫ hematopoietic chimeras reconstituted with cd69 Ϫ/Ϫ stem cells. Accordingly, mirn155 Ϫ/Ϫ mice have an impaired development of CD69 ϩ tTreg cells and overexpression of the miR-155-induced CD69 pathway, suggesting that both molecules might be concomitantly activated in a positive-feedback loop. Moreover, in vitro-inducible CD25 ϩ Treg (iTreg) cell development is inhibited in Il2r␥ Ϫ/Ϫ /cd69 Ϫ/Ϫ mice. Our data highlight the contribution of CD69 as a nonredundant key regulator of BIC/miR-155-dependent Treg cell development and homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

Sánchez-Díaz

Blanco-Domínguez

Lasarte

et al. 2017

Molecular and Cellular Biology

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“…The physiological role of this receptor, which is persistently expressed by infiltrating leukocytes in different chronic inflammatory diseases, has been studied in CD69-deficient mice in multiple different models of chronic inflammation (2)(3)(4)(5). Thus, we have previously described that CD69 Ϫ/Ϫ mice develop an exacerbated form of collagen-induced arthritis (CIA) (3), a Th1 and Th17 cell-mediated autoimmune condition.…”

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confidence: 99%

The Leukocyte Activation Receptor CD69 Controls T Cell Differentiation through Its Interaction with Galectin-1

Fuente

Cruz-Adalia

Martín

et al. 2014

Molecular and Cellular Biology

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f CD69 is involved in immune cell homeostasis, regulating the T cell-mediated immune response through the control of Th17 cell differentiation. However, natural ligands for CD69 have not yet been described. Using recombinant fusion proteins containing the extracellular domain of CD69, we have detected the presence of a ligand(s) for CD69 on human dendritic cells (DCs). Pulldown followed by mass spectrometry analyses of CD69-binding moieties on DCs identified galectin-1 as a CD69 counterreceptor. Surface plasmon resonance and anti-CD69 blocking analyses demonstrated a direct and specific interaction between CD69 and galectin-1 that was carbohydrate dependent. Functional assays with both human and mouse T cells demonstrated the role of CD69 in the negative effect of galectin-1 on Th17 differentiation. Our findings identify CD69 and galectin-1 to be a novel regulatory receptor-ligand pair that modulates Th17 effector cell differentiation and function. C D69, a C-type lectin, is a member of the natural killer (NK) receptor family and is induced early following activation of leukocytes (1). The physiological role of this receptor, which is persistently expressed by infiltrating leukocytes in different chronic inflammatory diseases, has been studied in CD69-deficient mice in multiple different models of chronic inflammation (2-5). Thus, we have previously described that CD69 Ϫ/Ϫ mice develop an exacerbated form of collagen-induced arthritis (CIA) (3), a Th1 and Th17 cell-mediated autoimmune condition. Moreover, in an experimental model of autoimmune myocarditis (EAM), CD69 negatively regulates cardiac inflammation through the regulation of heart-specific Th17 responses (4). In this regard, we have detected that CD69 modulates the in vitro differentiation of T cells toward the Th17 lineage through the activation of the Jak3/Stat5 inhibitory pathway (5). On the other hand, CD69 negatively regulates the chemotactic responses of effector lymphocytes and dendritic cells (DCs) to sphingosine 1 phosphate (S1P); CD69 can associate with S1P1 in the cell membrane and induce a conformation of S1P1 that favors its internalization and degradation (6-8). It is clear that the identification of cellular ligands for CD69 is a critical next step to better understand the physiological role of this receptor.Galectins are characterized by a common structural fold and a conserved carbohydrate recognition domain (CRD) with a high affinity for beta-galactosides (9). Despite being soluble proteins, galectins are also expressed on the cell surface due to their association with membrane glycoproteins. Thus, galectin-1 (Gal-1) is expressed by most activated but not resting T and B cells, and it is significantly upregulated in activated macrophages and T regulatory lymphocytes (10). In addition, tolerogenic DCs show a high expression of Gal-1 (11), which is rapidly downregulated in response to maturation signals. Furthermore, Gal-1-deficient DCs show a greater immunogenic potential and an impaired ability to halt the inflammatory phenomenon in a ...

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“…Histology of the large intestine was categorized as normal (score 0); mild colitis (score 1), with few inflammatory cells in the cLP, stroma edema, and a slight reduction of goblet cells; moderate colitis (score 2), with an intense inflammatory infiltration of the lamina propria, hyperplasia of crypts, and a marked reduction of goblet cells; or severe colitis (score 3), with a spillover of leukocytes beyond the mucosa into deeper layers of the colonic wall, complete loss of goblet cells, distortion of the mucosal architecture, erosions or ulcerations, and crypt abscesses as previously published. 44,45 CD4 T-cell isolation from cLP. CD4 T cells were isolated from the cLP of RAG À / À , CX 3 CR1 GFP/ þ Â RAG À / À , CX 3 CR1 GFP/GFP Â RAG À / À , LTa tm1Dch Â RAG À / À , and LtbR À / À Â RAG À / À animals.…”

Section: Methodsmentioning

confidence: 99%

CX3CR1+ cells facilitate the activation of CD4 T cells in the colonic lamina propria during antigen-driven colitis

et al. 2014

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Dendritic cells (DCs) and macrophages populate the intestinal lamina propria to initiate immune responses required for the maintenance of intestinal homeostasis. To investigate whether CX3CR1(+) phagocytes communicate with CD4 T cells during the development of transfer colitis, we established an antigen-driven colitis model induced by the adoptive transfer of DsRed OT-II cells in CX3CR1(GFP/+) × RAG(-/-) recipients challenged with Escherichia coli expressing ovalbumin (OVA) fused to a cyan fluorescent protein (CFP). After colonization of CX3CR1(GFP/+) × RAG(-/-) animals with red fluorescent E. coli pCherry-OVA, colonic CX3CR1(+) cells but not CD103(+) DCs phagocytosed E. coli pCherry-OVA. Degraded bacterial-derived antigens are transported by CD103(+) DCs to mesenteric lymph nodes (MLNs), where CD103(+) DCs prime naive T cells. In RAG(-/-) recipients reconstituted with OT II cells and gavaged with OVA-expressing E. coli, colonic CX3CR1(+) phagocytes are in close contact with CD4 T cells and presented bacterial-derived antigens to CD4 T cells to activate and expand effector T cells.

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CD69 Regulates Type I IFN-Induced Tolerogenic Signals to Mucosal CD4 T Cells That Attenuate Their Colitogenic Potential

Cited by 72 publications

References 56 publications

Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression

The Leukocyte Activation Receptor CD69 Controls T Cell Differentiation through Its Interaction with Galectin-1

CX3CR1+ cells facilitate the activation of CD4 T cells in the colonic lamina propria during antigen-driven colitis

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