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Β2 integrins rather than β1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung  Maya R. Karta, PhD, Peter S. Rosenthal,

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Presentation on theme: "Β2 integrins rather than β1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung  Maya R. Karta, PhD, Peter S. Rosenthal,"— Presentation transcript:

1 β2 integrins rather than β1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung  Maya R. Karta, PhD, Peter S. Rosenthal, BS, Andrew Beppu, BS, Christine Y. Vuong, BS, Marina Miller, MD, PhD, Sudipta Das, PhD, Richard C. Kurten, PhD, Taylor A. Doherty, MD, David H. Broide, MB, ChB  Journal of Allergy and Clinical Immunology  Volume 141, Issue 1, Pages e12 (January 2018) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Human ILC2s express CD18/CD11a (β2/αL) and CD29/CD49d (β1/α4) integrins. A, Representative ILC2 gating strategy from human lymph nodes. FSC, Forward scatter; SSC, side scatter. B, Frequency of ILC2s from CD45+ human PBMCs, lungs, and lung lymph nodes (LN). C-E, Summary of ILC2 adhesion molecule expression from PBMCs (n = 7; Fig 1, C), lung tissue (n = 8; Fig 1, D), and lymph nodes (LN; n = 7; Fig 1, E). F-H, Comparison of ILC2 and CD4+CRTH2+ cell adhesion molecule ΔgMFI from PBMCs (n = 5; Fig 1, F), lungs (n = 3; Fig 1, G), and lymph nodes (n = 5; Fig 1, H) of the same donor. Solid circles represent ILC2 populations, and open circles represent CD4+CRTH2+ populations. Data are depicted as box plots (whiskers, 10th-90th percentile) or individual points; the mean ± SEM is represented as a line. *P < .05, Student paired t test. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Adhesion molecule expression on mouse lung ILC2s. A, Representative gating strategy of mouse lung ILC2s. FSC, Forward scatter; SSC, side scatter. B and C, Mouse lung ILC2s (open circles) compared with lung CD4+Thy1.2+ cells (gray squares) in percentage adhesion molecule expression (Fig 2, B) and adhesion molecule ΔgMFI (Fig 2, C; n = 3). D and E, Comparison of mouse lung ILC2 percentage expression (Fig 2, D) and ΔgMFI (Fig 2, E) of adhesion molecules between naive mice (open circles) and Alternaria-challenged mice (solid circles; n = 7). Independent experiments are depicted as individual points; the mean ± SEM is represented as a line. *P < .05, **P < .01, and ***P < .001, Student t test. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 ILC2 numbers change in the bone marrow, blood, and lungs after Alternaria (Alt) challenge in wild-type and BMT mice. A-C, Total ILC2s from bone marrow (Fig 3, A), blood (Fig 3, B), and whole lung (Fig 3, C) from naive (white columns; n ≥ 23), 4-day Alternaria challenged (gray columns; n = 8), and 7-day Alternaria challenged (black columns; n ≥ 14) mice. CD45.1 or CD45.2 donor bone marrow was transplanted into CD45.2-irradiated recipient mice. D, Representative plots of BMT mouse blood ILC2 expression of CD45.1 and CD45.2. E, Total CD45.1 (black columns) and CD45.2 (white columns) blood cells from BMT mice. F and G, Total ILC2s from blood (Fig 3, F) and whole lung (Fig 3, G) from naive (n = 8) or Alternaria challenged (n = 4) BMT mice. H, Total lung Ki-67+ ILC2s from BMT mice. Data are summarized as bar graphs representing means ± SEMs. *P < .05, **P < .01, and ***P < .001, Student t test. NS, Not significant. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 In vivo blocking of CD18 diminishes Alternaria-induced ILC2 recruitment to the airways. A, Mice treated with anti-CD18 antibody (αCD18) or the isotype control and challenged with Alternaria (Alt). i.n., Intranasal; i.p., intraperitoneal. B, Total ILC2s per mouse whole lung (n ≥ 10). C, Representative plots of ILC2 Ki-67 and Annexin V expression and summary of the percentage of Ki-67+ ILC2s (n ≥ 10) and live Annexin V+ ILC2s (n ≥ 4) per mouse lung. D, Summary of total IL-5–, IL-13–, and IL-5/IL-13–producing ILC2s in the lung (n ≥ 4; data were log transformed for normalcy). E, Total number of sorted ILC2s adherent to ICAM-1–coated wells compared with control-coated wells with or without preincubation of ILC2s with αCD18 (2 independent experiments). F, Total ILC2s per lung of mice treated with or without Alternaria and with or without anti-CD11a antibody (n ≥ 6). Data are summarized as bar graphs or individual points; the mean ± SEM is represented as a line. *P < .05, **P < .01, and ***P < .001, Student t test. NS, Not significant. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 In vivo blocking of CD29 and CD49d does not alter Alternaria (Alt)-induced ILC2 recruitment. A-C, Total number of lung ILC2s (Fig 5, A), total Ki-67+ ILC2s (Fig 5, B), and live Annexin V+ ILC2s (Fig 5, C) per mouse treated ± anti-CD29 antibody (n ≥ 6). D, Percentage of human ILC2s expressing integrin β7 and both CD49d and β7 from PBMCs (white columns; n = 4), lung tissue (black columns; n = 3), and lymph nodes (gray columns; n = 4). E, Summary of the percentage of mouse lung ILC2s expressing CD49d and integrin β7 from both naive and Alternaria-challenged mice (n = 8). F-H, Total number of lung ILC2s (Fig 5, F), total Ki-67+ ILC2s (Fig 5, G), and live Annexin V+ ILC2s (Fig 5, H) per mouse treated with or without anti-CD49d antibody (n ≥ 5). The mean ± SEM represented as a line. *P < .05, **P < .01, and ***P < .001, Student t test. NS, Not significant. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 Representative adhesion molecule expression on human ILC2s. Representative histograms of peripheral blood (A), lung (B), and lung lymph node (C) human ILC2 levels of expression of CD18, CD11a, CD29, CD49d, CD62L, CD54, and CD106. Dotted histogram represents isotype control, and filled histogram represents adhesion molecule expression. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E2 Adhesion molecule expression on human ILC2s. Summary of the percentage of human ILC2s from PBMCs (white columns; n = 7), lungs (light gray columns; n = 8), and lung lymph nodes (LN; dark gray columns; n = 7) expressing CD18 and CD11a (A), CD29 and CD49d (B), CD62L (C), and CD54 and CD106 (D). Data are summarized as box plots (whiskers, 10th-90th percentiles). *P < .05, **P < .01, and ***P < .001, Student t test. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E3 Representative adhesion molecule expression on mouse lung ILC2s and CD4+ cells. Representative histograms of mouse lung ILC2 (A) and CD4+Thy1.2+ (B) levels of expression of CD18, CD11a, CD29, CD49d, CD62L, CD54, and CD106. Dotted histogram represents isotype control, and filled histogram represents adhesion molecule expression. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E4 Gating strategy for detection of ILC2s from mouse bone marrow, blood, lymph node, and spleen. Representative gating strategy for mouse ILC2 identification from bone marrow (A), blood (B), lung lymph nodes (C), and spleens (D) from both naive and Alternaria challenged mice sacrificed on day 7. The percentage of the population from the parent is noted in boldface. FSC, Forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E5 ILC2 numbers change in lung lymph nodes and spleens after 4- and 7-day Alternaria (Alt) challenge in mice. A and B, Total ILC2s from lung lymph nodes (Fig E5, A) and spleens (Fig E5, B) from naive (white columns; n ≥ 8), 4-day Alternaria challenged (gray columns; n ≥ 4), and 7-day Alternaria-challenged (black columns; n ≥ 4) mice. C-G, Total CD45+ leukocytes from bone marrow (Fig E5, C), blood (Fig E5, D), whole lungs (Fig E5, E), lung lymph nodes (Fig E5, F), and spleens (Fig E5, G) from naive (white bars) and 4-day (gray bars) and 7-day Alternaria-challenged mice (black bars). Data are summarized as bar graphs representing means ± SEMs. *P < .05, **P < .01, and ***P < .001, Student t test. NS, Not significant. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E6 Gating strategy for BMT mouse lung ILC2s. CD45.1 or CD45.2 donor bone marrow was transplanted into CD45.2-irradiated recipient mice. A-C, Representative gating strategy for naive (Fig E6, A) or Alternaria-challenged (Fig E6, B) CD45.1 BMT mouse lung ILC2s and naive CD45.2 BMT mouse lung ILC2s (Fig E6, C). The percentage of the population from the parent is noted in boldface. FSC, Forward scatter; SSC, side scatter. D, Percentage of lung Ki-67+ ILC2s expressing either CD45.1 or CD45.2 from naive (n = 8) and Alternaria (Alt)-challenged (n = 4) BMT mice. Data are summarized as bar graphs representing means ± SEMs. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E7 αCD18 antibody had no effect on IL-5– and IL-13–expressing ILC2 totals in the mouse lung after Alternaria (Alt) challenge. Mice treated with or without an αCD18 antibody were challenged with Alternaria over a 7-day period. Summary of the total of IL-5–producing (A), IL-13–producing (B), and IL-5 and IL-13–producing (C) ILC2s in the lung (black bars; n ≥ 4) compared with total ILC2s in the lungs (white bars; n ≥ 10). Data are summarized as bar graphs representing means ± SEMs. Journal of Allergy and Clinical Immunology  , e12DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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