Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization Jamie A. Leggat, PhD, Deena L. Gibbons, PhD, Syeda.

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Presentation transcript:

Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization Jamie A. Leggat, PhD, Deena L. Gibbons, PhD, Syeda F.Y. Haque, BSc, Adrian L. Smith, PhD, James W. Wells, PhD, Katherine Choy, BVSc, Clare M. Lloyd, PhD, Adrian C. Hayday, PhD, Alistair Noble, PhD Journal of Allergy and Clinical Immunology Volume 122, Issue 5, Pages 1014-1021.e4 (November 2008) DOI: 10.1016/j.jaci.2008.08.011 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-12 + IL-18 induces non–antigen-specific, rapid IFN-γ producing effectors. A, Proliferation of CD8 cells separated into CD44lo and CD44hi fractions and cultured with cytokines as indicated. B, CD44hi CD8 Tms were labeled with CFSE before 3 days of culture in IL-12 ± IL-18 as indicated, washed, and restimulated with IL-12 + IL-18 before IFN-γ flow cytometry. C, CFSE-labeled OT-1 CD8 T lymphocytes were stimulated with IL-12 + IL-18 or antigen (SII peptide) and stained for CD25 after 3 days. D, Fresh CD8 Tms (unprimed) or CD8 Tms expanded for 4 days in IL-12 + IL-18 (effectors) were stimulated for 5 or 15 hours with IL-12/IL-18/monensin before IFN-γ staining. E, CD40L staining after priming/restimulation with cytokines: CD8 T lymphocytes cultured with IL-12 + IL-18 or anti-CD3/CD28 for 5 days were restimulated as initially. N = 3 in all panels. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Bidirectional stimulation between CD8 Tms and DCs. A and B, IL-12 induction by OT-1 naive/memory CD8 T lymphocytes stimulated with DCs + irrelevant peptide (RGY), relevant peptide (SII), or whole ovalbumin ± CpG (TLR9 ligand). “No T cells” and “no DC” cultures contained ovalbumin + CpG. In B, antibodies to CD40L/IFN-γ were added to peptide + CpG cultures. IL-12p70 in 24-hour supernatants from 3 (A) or 4 (B) experiments. C, CD8 T lymphocytes enhance IL-12 in vivo. Mice were depleted of CD8 T lymphocytes, injected with 75 μg SEB or PBS, and serum IL-12p70 was measured 4 hours later (n = 7). D, CD8 Tms proliferate in response to TLR ligands if DCs are present. CD44hi/CD44lo CD8 T lymphocytes were stimulated ± DC/TLR agonists. Mean proliferation ± SD of triplicates is shown; 1 of 3 similar experiments. E, CpG treatment expands and primes lung CD8 Tms. Lung or mediastinal lymph node cells from mice treated 3 and 6 days previously with 10 μg CpG intranasally (right) or PBS (left) were CD44-labeled and stimulated with anti-CD3/CD28 or IL-12/IL-18. IFN-γ staining in gated CD8 T lymphocytes is shown (n = 3). in, Intranasal; LN, lymph node. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Infection with a gut parasite results in enhanced maturity of CD8 Tm populations. A, B6 mice were infected orally with 1000 E vermiformis oocysts on day 0, and subsequently immunized and challenged with ovalbumin (OVA) or PBS. Spleen cells harvested on day 31 or 52 were stimulated with anti-CD3/CD28 or IL-12 + IL-18. Percent IFN-γ+ cells within CD8+CD44hi populations shown (n = 16). B, As in A, but different doses of E vermiformis oocysts were used; IFN-γ from day 31 CD8 T lymphocytes stimulated with IL-12 + IL-18 is shown (n = 8). ∗P < .05; ∗∗P < .01; ∗∗∗P < .005. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CD8 Tms activate each other, resulting in imprinting of nonspecific populations by specific immunity. A, OT-1 CD8 Tms were mixed with CFSE-labeled nonspecific (B6) CD8 Tms and DCs ± SII peptide overnight. Percent IFN-γ+ in SII-specific (CFSE-) and bystander (CFSE+) populations is shown (n = 3). B, CFSE-labeled nonspecific CD8 T lymphocytes were injected intravenously into OT-1 mice immunized with PBS/SII or into B6 mice given peptide as control. Bystander CD8 division (CFSE dilution) in lymph nodes after 3 days is shown (upper panels; n = 3). Vα2/Vβ5 TCR staining in bystander-activated group is shown in lower panels. C, An antigen-specific CD8 response leaves an imprint on non–antigen-specific CD8 Tms. B6 mice given PBS or OT-1 cells were immunized with SII + anti-CD40 (vaccine) as indicated. Left panel, Percent SII-specific CD8 in blood. Right panel, IFN-γ staining in gated non–antigen-specific (Pentamer-) CD8 T lymphocytes (n = 4). ∗P < .05; ∗∗∗P < .005. ip, Intraperitoneal; iv, intravenous; LN, lymph node; SC, subcutaneous; Tm, memory T lymphocyte. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 CD8 Tms inhibit allergic airway disease mediated entirely by CD4 T cells in a nonspecific fashion. CD8β-depleted or control (IgG) mice were given 5 × 106 OT-2 CD4 transgenic cells, immunized with ISQ peptide/alum and challenged intranasally with ISQ on days 10 to 14. A, Serum total IgE levels. B, Numbers of eosinophils, neutrophils, and T cells in BAL fluid on day 15. C, Numbers of BAL T1/ST2+ CD4+ TH2 cells. D, Airway reactivity to methacholine; all n = 6. E-H, Mice were injected with PBS, SII/anti-CD40 vaccine, and OT-1 CD8 T lymphocytes as in Fig 4, C. E, Day 14 ovalbumin-specific CD8 T lymphocytes in blood. Mice were sensitized and challenged with ISQ/OT-2 cells as in A, starting 7 days after CD8 transfer. BAL cell counts (F), TH2 cells (G), and airway reactivity (H) are shown after 15 days (n = 6). ∗P < .05; ∗∗P < .01. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Model for regulation of allergy before and after antigenic/microbial exposure. Pink circle represents a newly encountered allergen peptide. Lack of mature CD8 Tms in a clean environment results in low innate phase cytokines and TH2 development. In a dirty environment, primed CD8 Tms are stimulated by cross-reactivity with allergen or via bystander activation and inhibit TH2 responses by eliciting TH1-promoting cytokines. Tm, Memory T lymphocyte. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Early IFN-γ synthesis in central and effector memory CD8 Tms Early IFN-γ synthesis in central and effector memory CD8 Tms. A, CD8 Tms (CD44hi) are the major source of TCR-triggered early IFN-γ. CD8 T cells purified from tissues of untreated mice were stimulated with anti-CD3/CD28 for 5 hours and stained for CD44 and intracellular IFN-γ. Gated CD8+ events are shown. Data refer to percent IFN-γ+ cells in total CD8 population. B, CD8 but not CD4 T cells from unprimed mice produce IFN-γ after primary stimulation with cytokines alone. Lymph node CD4 or CD8 T cells were stained for CD44 (memory marker) and CD62L (lymph node homing receptor) and then stimulated with indicated cytokines for 5 hours before intracellular IFN-γ analysis. C, Both central memory (CD44hi CD62Lhi) and effector memory (CD44hi CD62Llo) CD8 cells produce early IFN-γ after IL-12 + IL-18 stimulation. Splenic CD4 or CD8 cells were stained for CD62L and CD44 before IL-12/IL-18 stimulation. Spleen contained both central and effector memory cells. Percent IFN-γ+ cells within each subpopulation are shown. D, Time course of IFN-γ secretion from cultures of fractionated CD44hi and CD44lo CD8 cells stimulated with IL-12/IL-18 or anti-CD3/28. Data in A and B are representative of 3 experiments; data in C and D are means ± SEMs from 3 independent experiments. ∗P < .05; ∗∗∗P < .005. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IL -12+ IL-18 induces perforin expression in CD8 Tms IL -12+ IL-18 induces perforin expression in CD8 Tms. Splenic CD8 T cells were labeled with anti–CD44-APC, washed, and cultured with IL-12 + IL-18 (10 ng/mL each) or platebound anti-CD3 + IL-2 or were unstimulated for 3 days. Cells were then fixed, permeabilized, with 0.1% Triton X100 (Sigma, Poole, UK), and stained with antiperforin-phycoerythrin or isotype control antibody before flow cytometry. Intracellular perforin staining in gated CD44hi (memory CD8, upper graph) or naive CD8 (CD44lo, lower graph) is shown. Data are representative of 3 experiments. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Proportions of CD8 T cells, total DC (CD11C+) and plasmacytoid DC (mPDCA-1+) in spleen 1 day after intraperitoneal injection of C57BL/6 mice with 75 μg anti-CD8β or control antibody. Journal of Allergy and Clinical Immunology 2008 122, 1014-1021.e4DOI: (10.1016/j.jaci.2008.08.011) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions