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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.

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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 provides a selective advantage to effector CD4+ T cells. Equal numbers of LACK-specific CX3CR1gfp/gfp and CX3CR1+/gfp Th2 or Th1 cells were coinjected into WT mice at day 0. Recipients were sensitized with LACK or PBS at days 1 and 4 and analyzed at day 3 (A, C, and D) or 7 (B and D). (A) Donor cells were analyzed in skin by flow cytometry. Data show representative flow cytometry profiles (top). Data show mean frequencies ± SEM of donor Th1 (bottom left) or Th2 (bottom right) cells among the CD4+ T cell population. One representative experiment out of two is shown (n = 6 mice per group). (B) Donor cells were analyzed in skin by flow cytometry (top). Data show donor cell frequency of Th1 (bottom left) or Th2 (bottom right) in individual mice with horizontal bars indicating the mean from three experiments (n = 16 mice per group). *, P < 0.05. (C) 18 h before sacrifice, recipient mice were injected with BrdU, and donor cells were analyzed by flow cytometry after staining with anti-BrdU, anti-Thy1.1, anti-Thy1.2, anti-CD4, and anti-CD45 antibodies. Data show cell frequency of donor Th1 or Th2 cells in individual mice with horizontal bars indicating the mean in LACK-sensitized (n = 4 mice) and PBS-sensitized mice (n = 2–3 mice). One representative experiment out of two is shown. (D) Donor cells were analyzed in draining LNs (dLN) and skin by flow cytometry for GFP expression at days 3 and 7. Data show representative flow cytometry profiles after aggregating files from individual mice (top; n = 6 mice per group). One experiment out of three is shown. Histograms show mean frequencies ± SEM of GFP+ cells among Th1 (left) or Th2 (right) donor cells (n = 12 mice per group at day 3 and n = 18 mice at day 7).
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fig4: CX3CR1 provides a selective advantage to effector CD4+ T cells. Equal numbers of LACK-specific CX3CR1gfp/gfp and CX3CR1+/gfp Th2 or Th1 cells were coinjected into WT mice at day 0. Recipients were sensitized with LACK or PBS at days 1 and 4 and analyzed at day 3 (A, C, and D) or 7 (B and D). (A) Donor cells were analyzed in skin by flow cytometry. Data show representative flow cytometry profiles (top). Data show mean frequencies ± SEM of donor Th1 (bottom left) or Th2 (bottom right) cells among the CD4+ T cell population. One representative experiment out of two is shown (n = 6 mice per group). (B) Donor cells were analyzed in skin by flow cytometry (top). Data show donor cell frequency of Th1 (bottom left) or Th2 (bottom right) in individual mice with horizontal bars indicating the mean from three experiments (n = 16 mice per group). *, P < 0.05. (C) 18 h before sacrifice, recipient mice were injected with BrdU, and donor cells were analyzed by flow cytometry after staining with anti-BrdU, anti-Thy1.1, anti-Thy1.2, anti-CD4, and anti-CD45 antibodies. Data show cell frequency of donor Th1 or Th2 cells in individual mice with horizontal bars indicating the mean in LACK-sensitized (n = 4 mice) and PBS-sensitized mice (n = 2–3 mice). One representative experiment out of two is shown. (D) Donor cells were analyzed in draining LNs (dLN) and skin by flow cytometry for GFP expression at days 3 and 7. Data show representative flow cytometry profiles after aggregating files from individual mice (top; n = 6 mice per group). One experiment out of three is shown. Histograms show mean frequencies ± SEM of GFP+ cells among Th1 (left) or Th2 (right) donor cells (n = 12 mice per group at day 3 and n = 18 mice at day 7).

Mentions: To decipher the mechanisms accounting for the role of CX3CR1 expression by T helper cells in skin inflammation, we monitored the recruitment and proliferative capacities of both CX3CR1-proficient and -deficient, LACK-specific Th1 and Th2 cells upon coinjection into WT mice that were exposed to LACK and further fed with BrdU. 3 d after antigen exposure, although Th1 and Th2 donor cells of both genotypes had not yet incorporated BrdU (not depicted), CX3CR1-proficient and -deficient, LACK-specific donor cells were detected at the same frequency in skin, suggesting that early migration of effector T cells into the skin did not require CX3CR1 (Fig. 4 A). It is worth noting that antigen-induced recruitment of LACK-specific Th1 cells was more pronounced than recruitment of Th2 cells as early as 3 d after antigen exposure. In sharp contrast, frequencies of CX3CR1-proficient donor cells outnumbered CX3CR1-deficient cells on day 7 (Fig. 4 B). However, donor cells of both genotypes proliferated at the same rate (Fig. 4 C). Therefore, as observed for naive T cells, CX3CR1 deficiency neither affects the early recruitment nor the proliferation of Th1 and Th2 effector cells.


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 provides a selective advantage to effector CD4+ T cells. Equal numbers of LACK-specific CX3CR1gfp/gfp and CX3CR1+/gfp Th2 or Th1 cells were coinjected into WT mice at day 0. Recipients were sensitized with LACK or PBS at days 1 and 4 and analyzed at day 3 (A, C, and D) or 7 (B and D). (A) Donor cells were analyzed in skin by flow cytometry. Data show representative flow cytometry profiles (top). Data show mean frequencies ± SEM of donor Th1 (bottom left) or Th2 (bottom right) cells among the CD4+ T cell population. One representative experiment out of two is shown (n = 6 mice per group). (B) Donor cells were analyzed in skin by flow cytometry (top). Data show donor cell frequency of Th1 (bottom left) or Th2 (bottom right) in individual mice with horizontal bars indicating the mean from three experiments (n = 16 mice per group). *, P < 0.05. (C) 18 h before sacrifice, recipient mice were injected with BrdU, and donor cells were analyzed by flow cytometry after staining with anti-BrdU, anti-Thy1.1, anti-Thy1.2, anti-CD4, and anti-CD45 antibodies. Data show cell frequency of donor Th1 or Th2 cells in individual mice with horizontal bars indicating the mean in LACK-sensitized (n = 4 mice) and PBS-sensitized mice (n = 2–3 mice). One representative experiment out of two is shown. (D) Donor cells were analyzed in draining LNs (dLN) and skin by flow cytometry for GFP expression at days 3 and 7. Data show representative flow cytometry profiles after aggregating files from individual mice (top; n = 6 mice per group). One experiment out of three is shown. Histograms show mean frequencies ± SEM of GFP+ cells among Th1 (left) or Th2 (right) donor cells (n = 12 mice per group at day 3 and n = 18 mice at day 7).
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fig4: CX3CR1 provides a selective advantage to effector CD4+ T cells. Equal numbers of LACK-specific CX3CR1gfp/gfp and CX3CR1+/gfp Th2 or Th1 cells were coinjected into WT mice at day 0. Recipients were sensitized with LACK or PBS at days 1 and 4 and analyzed at day 3 (A, C, and D) or 7 (B and D). (A) Donor cells were analyzed in skin by flow cytometry. Data show representative flow cytometry profiles (top). Data show mean frequencies ± SEM of donor Th1 (bottom left) or Th2 (bottom right) cells among the CD4+ T cell population. One representative experiment out of two is shown (n = 6 mice per group). (B) Donor cells were analyzed in skin by flow cytometry (top). Data show donor cell frequency of Th1 (bottom left) or Th2 (bottom right) in individual mice with horizontal bars indicating the mean from three experiments (n = 16 mice per group). *, P < 0.05. (C) 18 h before sacrifice, recipient mice were injected with BrdU, and donor cells were analyzed by flow cytometry after staining with anti-BrdU, anti-Thy1.1, anti-Thy1.2, anti-CD4, and anti-CD45 antibodies. Data show cell frequency of donor Th1 or Th2 cells in individual mice with horizontal bars indicating the mean in LACK-sensitized (n = 4 mice) and PBS-sensitized mice (n = 2–3 mice). One representative experiment out of two is shown. (D) Donor cells were analyzed in draining LNs (dLN) and skin by flow cytometry for GFP expression at days 3 and 7. Data show representative flow cytometry profiles after aggregating files from individual mice (top; n = 6 mice per group). One experiment out of three is shown. Histograms show mean frequencies ± SEM of GFP+ cells among Th1 (left) or Th2 (right) donor cells (n = 12 mice per group at day 3 and n = 18 mice at day 7).
Mentions: To decipher the mechanisms accounting for the role of CX3CR1 expression by T helper cells in skin inflammation, we monitored the recruitment and proliferative capacities of both CX3CR1-proficient and -deficient, LACK-specific Th1 and Th2 cells upon coinjection into WT mice that were exposed to LACK and further fed with BrdU. 3 d after antigen exposure, although Th1 and Th2 donor cells of both genotypes had not yet incorporated BrdU (not depicted), CX3CR1-proficient and -deficient, LACK-specific donor cells were detected at the same frequency in skin, suggesting that early migration of effector T cells into the skin did not require CX3CR1 (Fig. 4 A). It is worth noting that antigen-induced recruitment of LACK-specific Th1 cells was more pronounced than recruitment of Th2 cells as early as 3 d after antigen exposure. In sharp contrast, frequencies of CX3CR1-proficient donor cells outnumbered CX3CR1-deficient cells on day 7 (Fig. 4 B). However, donor cells of both genotypes proliferated at the same rate (Fig. 4 C). Therefore, as observed for naive T cells, CX3CR1 deficiency neither affects the early recruitment nor the proliferation of Th1 and Th2 effector cells.

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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