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CX₃CL1 (fractalkine) and its receptor CX₃CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin.

Staumont-Sallé D, Fleury S, Lazzari A, Molendi-Coste O, Hornez N, Lavogiez C, Kanda A, Wartelle J, Fries A, Pennino D, Mionnet C, Prawitt J, Bouchaert E, Delaporte E, Glaichenhaus N, Staels B, Julia V, Dombrowicz D - J. Exp. Med. (2014)

Bottom Line: CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD.Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor.Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, France European Genomic Institute of Diabetes, 59045 Lille, France Department of Dermatology, Claude-Huriez Hospital, 59037 Lille, France.

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CX3CR1 expression regulates both Th1- and Th2-induced skin inflammation. (A) CSFE-labeled CX3CR1+/+ WT15 Thy1.1+/+ CD4+ T cells were injected i.v. into CX3CR1gfp/gfp or CX3CR1+/gfp mice 1 d before epicutaneous sensitization with LACK. Donor cells were analyzed by flow cytometry 5 d later in inguinal LNs after gating onto CD4+ Thy1.1+ cells. Data show one representative flow cytometry profile of CFSE staining with numbers indicating frequencies of dividing donor cells ± SEM (n = 6). (B) CSFE-labeled CX3CR1+/gfp Thy1.1+/− and CX3CR1gfp/gfp Thy1.1+/+ WT15 CD4+ T cells were coinjected i.v. into WT Thy1.1−/− Thy1.2+/+ mice 1 d before LACK or PBS epicutaneous sensitization. Donor cells were analyzed by flow cytometry 4 d later in inguinal LNs after gating CD4+ Thy1.1+ cells. Data show a representative flow cytometry profile of CFSE staining with numbers indicating dividing CX3CR1+/+ and CX3CR1gfp/gfp donor cells (n = 5 mice in each group). (C and D) WT mice were injected at day −1 with LACK-specific CX3CR1gfp/gfp or CX3CR1+/gfp Th1 or Th2 cells, sensitized for one single week with LACK or PBS at day 0, and further analyzed at day 7. (C) Epidermal thickness. (D) Eosinophil and mast cell numbers in dermis at the site of sensitization. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. *, P < 0.05.
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fig3: CX3CR1 expression regulates both Th1- and Th2-induced skin inflammation. (A) CSFE-labeled CX3CR1+/+ WT15 Thy1.1+/+ CD4+ T cells were injected i.v. into CX3CR1gfp/gfp or CX3CR1+/gfp mice 1 d before epicutaneous sensitization with LACK. Donor cells were analyzed by flow cytometry 5 d later in inguinal LNs after gating onto CD4+ Thy1.1+ cells. Data show one representative flow cytometry profile of CFSE staining with numbers indicating frequencies of dividing donor cells ± SEM (n = 6). (B) CSFE-labeled CX3CR1+/gfp Thy1.1+/− and CX3CR1gfp/gfp Thy1.1+/+ WT15 CD4+ T cells were coinjected i.v. into WT Thy1.1−/− Thy1.2+/+ mice 1 d before LACK or PBS epicutaneous sensitization. Donor cells were analyzed by flow cytometry 4 d later in inguinal LNs after gating CD4+ Thy1.1+ cells. Data show a representative flow cytometry profile of CFSE staining with numbers indicating dividing CX3CR1+/+ and CX3CR1gfp/gfp donor cells (n = 5 mice in each group). (C and D) WT mice were injected at day −1 with LACK-specific CX3CR1gfp/gfp or CX3CR1+/gfp Th1 or Th2 cells, sensitized for one single week with LACK or PBS at day 0, and further analyzed at day 7. (C) Epidermal thickness. (D) Eosinophil and mast cell numbers in dermis at the site of sensitization. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. *, P < 0.05.

Mentions: As CX3CR1 is expressed by various myeloid cells, such as blood monocytes, DC progenitors, plasmacytoid DCs, and macrophages (Bar-On et al., 2010; Kim et al., 2011; Zhang et al., 2012), we next assessed whether antigen presentation was affected in the absence of CX3CR1. To this aim, antigen-specific CD4+ T cells from WT15 TCR transgenic mice (Wang et al., 2001) were labeled with CSFE and injected into both CX3CR1+/gfp and CX3CR1gfp/gfp mice that were further sensitized via epicutaneous LACK administration. Frequencies of divided antigen-specific CD4+ T cells in the draining LN were comparable in both CX3CR1+/gfp and CX3CR1gfp/gfp mice (Fig. 3 A), suggesting that upon epicutaneous sensitization, CX3CR1 deficiency does not affect antigen presentation. We next investigated whether CX3CR1 deficiency affected T cell proliferation induced upon epicutaneous antigen sensitization. To address this issue, we generated Thy1+/− CX3CR1+/gfp and Thy1+/+ CX3CR1gfp/gfp LACK-specific TCR transgenic mice that, respectively, expressed the Thy1.1 and Thy1.2 antigens or the Thy1.1 antigen only. CD4+ T cells from both genotypes were prepared, stained with CSFE and coinjected into WT Thy1.1−/− Thy1.2+/+ mice. Upon epicutaneous sensitization with LACK, frequencies of dividing CX3CR1+/gfp and CX3CR1gfp/gfp WT15 cells were comparable (Fig. 3 B). Altogether these results suggest that CX3CR1 deficiency does not alter naive T cell proliferation.


CX₃CL1 (fractalkine) and its receptor CX₃CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin.

Staumont-Sallé D, Fleury S, Lazzari A, Molendi-Coste O, Hornez N, Lavogiez C, Kanda A, Wartelle J, Fries A, Pennino D, Mionnet C, Prawitt J, Bouchaert E, Delaporte E, Glaichenhaus N, Staels B, Julia V, Dombrowicz D - J. Exp. Med. (2014)

CX3CR1 expression regulates both Th1- and Th2-induced skin inflammation. (A) CSFE-labeled CX3CR1+/+ WT15 Thy1.1+/+ CD4+ T cells were injected i.v. into CX3CR1gfp/gfp or CX3CR1+/gfp mice 1 d before epicutaneous sensitization with LACK. Donor cells were analyzed by flow cytometry 5 d later in inguinal LNs after gating onto CD4+ Thy1.1+ cells. Data show one representative flow cytometry profile of CFSE staining with numbers indicating frequencies of dividing donor cells ± SEM (n = 6). (B) CSFE-labeled CX3CR1+/gfp Thy1.1+/− and CX3CR1gfp/gfp Thy1.1+/+ WT15 CD4+ T cells were coinjected i.v. into WT Thy1.1−/− Thy1.2+/+ mice 1 d before LACK or PBS epicutaneous sensitization. Donor cells were analyzed by flow cytometry 4 d later in inguinal LNs after gating CD4+ Thy1.1+ cells. Data show a representative flow cytometry profile of CFSE staining with numbers indicating dividing CX3CR1+/+ and CX3CR1gfp/gfp donor cells (n = 5 mice in each group). (C and D) WT mice were injected at day −1 with LACK-specific CX3CR1gfp/gfp or CX3CR1+/gfp Th1 or Th2 cells, sensitized for one single week with LACK or PBS at day 0, and further analyzed at day 7. (C) Epidermal thickness. (D) Eosinophil and mast cell numbers in dermis at the site of sensitization. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. *, P < 0.05.
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fig3: CX3CR1 expression regulates both Th1- and Th2-induced skin inflammation. (A) CSFE-labeled CX3CR1+/+ WT15 Thy1.1+/+ CD4+ T cells were injected i.v. into CX3CR1gfp/gfp or CX3CR1+/gfp mice 1 d before epicutaneous sensitization with LACK. Donor cells were analyzed by flow cytometry 5 d later in inguinal LNs after gating onto CD4+ Thy1.1+ cells. Data show one representative flow cytometry profile of CFSE staining with numbers indicating frequencies of dividing donor cells ± SEM (n = 6). (B) CSFE-labeled CX3CR1+/gfp Thy1.1+/− and CX3CR1gfp/gfp Thy1.1+/+ WT15 CD4+ T cells were coinjected i.v. into WT Thy1.1−/− Thy1.2+/+ mice 1 d before LACK or PBS epicutaneous sensitization. Donor cells were analyzed by flow cytometry 4 d later in inguinal LNs after gating CD4+ Thy1.1+ cells. Data show a representative flow cytometry profile of CFSE staining with numbers indicating dividing CX3CR1+/+ and CX3CR1gfp/gfp donor cells (n = 5 mice in each group). (C and D) WT mice were injected at day −1 with LACK-specific CX3CR1gfp/gfp or CX3CR1+/gfp Th1 or Th2 cells, sensitized for one single week with LACK or PBS at day 0, and further analyzed at day 7. (C) Epidermal thickness. (D) Eosinophil and mast cell numbers in dermis at the site of sensitization. Data are expressed as mean ± SEM (n = 6–10 animals per group). One out of two independent experiments is shown for each panel. *, P < 0.05.
Mentions: As CX3CR1 is expressed by various myeloid cells, such as blood monocytes, DC progenitors, plasmacytoid DCs, and macrophages (Bar-On et al., 2010; Kim et al., 2011; Zhang et al., 2012), we next assessed whether antigen presentation was affected in the absence of CX3CR1. To this aim, antigen-specific CD4+ T cells from WT15 TCR transgenic mice (Wang et al., 2001) were labeled with CSFE and injected into both CX3CR1+/gfp and CX3CR1gfp/gfp mice that were further sensitized via epicutaneous LACK administration. Frequencies of divided antigen-specific CD4+ T cells in the draining LN were comparable in both CX3CR1+/gfp and CX3CR1gfp/gfp mice (Fig. 3 A), suggesting that upon epicutaneous sensitization, CX3CR1 deficiency does not affect antigen presentation. We next investigated whether CX3CR1 deficiency affected T cell proliferation induced upon epicutaneous antigen sensitization. To address this issue, we generated Thy1+/− CX3CR1+/gfp and Thy1+/+ CX3CR1gfp/gfp LACK-specific TCR transgenic mice that, respectively, expressed the Thy1.1 and Thy1.2 antigens or the Thy1.1 antigen only. CD4+ T cells from both genotypes were prepared, stained with CSFE and coinjected into WT Thy1.1−/− Thy1.2+/+ mice. Upon epicutaneous sensitization with LACK, frequencies of dividing CX3CR1+/gfp and CX3CR1gfp/gfp WT15 cells were comparable (Fig. 3 B). Altogether these results suggest that CX3CR1 deficiency does not alter naive T cell proliferation.

Bottom Line: CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD.Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor.Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, France European Genomic Institute of Diabetes, 59045 Lille, France Department of Dermatology, Claude-Huriez Hospital, 59037 Lille, France.

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