Research ArticleIMMUNOLOGY

Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring

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Science Advances  29 May 2019:
Vol. 5, no. 5, eaav3058
DOI: 10.1126/sciadv.aav3058
  • Fig. 1 Maternal helminth infection confers systemic protective immunity against Nb to pups via nursing.

    (A) Female BALB/c mice were infected with 500 × Nb L3 and, 7 days PI, were cleared of Nb by a 5-day oral treatment with ivermectin; at day 21 PI, mice were mated and immunity in subsequent pups was established at various times after birth and/or Nb infection. (B) Total splenocyte cellularity in 14-day-old offspring. (C) Total numbers of CD+CD4+ T cells and activated T effector CD4 T cell populations (CD3+C0D4+CD44+CD62Llo) in 14-day-old offspring. (D) Intestinal worm burdens at day 5 PI of pups born to NvM or NbM mothers and infected with 250 × Nb L3 when 14 days old. (E) NvM and NbM offspring anti-CD3 restimulated splenocyte IL-13 secretion, lung tissue homogenate levels of IL-13 and IL-13+CD3+CD4+ T cells/MST, and Nb-specific serum immunoglobulin G1 (IgG1) at day 5 after Nb infection. OD405nm, optical density at 405 nm. (F) Worm burdens of NvM and NbM offspring infected when 14 days old and euthanized at day 5 PI following fostering on NvM or NbM dams at 3 days old. (G) Worm burdens of NvM and NbM offspring infected when 14 days old and euthanized at day 5 PI following fostering on WT or IL-4Rα−/− NvM and NbM dams. (H) NvM pups fostered by either NvM or NbM anti-CD3 restimulated splenocyte IL-13 secretion, lung tissue homogenate levels of IL-13 and IL-13+CD3+CD4+ T cells/MST, and Nb-specific serum IgG1 at day 5 after Nb infection. All data are representative of a minimum of two experimental repeats. *P < 0.05, **P < 0.01, and ***P < 0.001.

  • Fig. 2 Protection in NbM pups is maternal B cell dependent but not antibody dependent.

    (A) Nb-specific IgG1 levels in breast milk taken from the stomach of pups nursed by NvM or NbM. (B) Intestinal worm burdens at day 5 PI of NvM offspring infected at 14 days old with 250 × Nb L3 following intravenous administration of 150 μl of heat-inactivated serum from either NvM or NbM. (C) Intestinal worm burdens and Nb-specific serum IgG1 levels at day 5 PI of NvM offspring infected at 14 days old with 250 × Nb L3 after being fostered on either WT and IgMi NbM mice or WT and IgMi maternal Nb-specific serum IgG1 levels. (D) Three-day-old NvM pups were fostered on WT NvM/NbM or μMT NvM/NbM dams. Pups were infected when 14 days old with 250 × Nb L3 and euthanized at day 5 PI. Offspring intestinal worm burden was analyzed, and MST IL-13+CD3+CD4+ T cells were quantified at day 5 PI. (E) Intestinal worm burdens at day 5 PI of NvM offspring infected at 14 days old with 250 × Nb L3 after being fostered on either WT or B cell–IL-4Rα–deficient (MB1creIL-4Rα−/lox) dams. All data are representative of a minimum of two experimental repeats. *P < 0.05 and **P < 0.01.

  • Fig. 3 Offspring acquire, via nursing, persistent protection from Nb related to acquisition of a population of maternally derived CD4 T cells with a heightened TH2 responsiveness following Nb infection.

    (A) Three-day-old NvM Thy1.2+ pups were fostered on Thy1.1+ WT NvM/NbM dams. Eight-week-old NvM Thy1.2+ mice that had been fostered on either NvM or NbM Thy1.1+ dams were infected with 500 × Nb L3 and euthanized at day 5 PI. (B) Intestinal worm burdens in offspring at day 5 PI in 8-week-old mice born to either NvM or NbM were established. (C to F) Numbers and proportions of offspring endogenous (Thy1.2+Thy1.1) and maternally derived (Thy1.1+Thy1.2) lung (C) Thy1+CD3+CD4+, (D) CD44+CD62Llo, (E) T1/ST2+, and (F) IL-13+ expressing T cell populations. All data are representative of a minimum of two experimental repeats. *P < 0.05 and **P < 0.01.

  • Fig. 4 Offspring acquire, via nursing, persistent protection from Nb related to raised TH2 CD4 T cell responses following Nb infection in an allogeneic setting.

    (A) Three-day-old NvM C57BL/6 pups were fostered on BALB/c NvM or WT NbM dams before being infected at 8 weeks old with 500 × Nb L3 and euthanized at day 5 PI. (B) Intestinal worm burdens at day 5 PI in 8-week-old mice born to either NvM or NbM were established. (C) Numbers of lung CD3+CD4+, ST2+, IL-13+, and CD44+CD62Llo expressing T cell populations were quantified. All data are representative of a minimum of two experimental repeats. *P < 0.05, **P < 0.01, and ***P < 0.001.

  • Fig. 5 IL-4Rα−/− offspring nursed on NbM dams have enhanced lymphocyte-mediated immunity against Nb infection.

    (A) Three-day-old IL-4Rα−/− pups were fostered on either WT NvM or NbM dams. Offspring were infected when 14 days old with 250 × Nb L3 and euthanized at day 5 PI, and intestinal worm burdens were quantified. (B) Nb-specific serum IgG1, anti-CD3 restimulated splenocyte IL-13, lung homogenate levels of IL-13, and CD3+CD4+IL-13+ T cells/MST were quantified in IL-4Rα−/− pups. (C) Numbers of immune cells in breast milk pellets from the stomachs of 10-day-old pups nursed by WT NvM or NbM dams. All data are representative of a minimum of two experimental repeats. *P < 0.05, **P < 0.01, and ***P < 0.001.

  • Fig. 6 Maternally derived type 2 CD4+T cells are enriched in NbM dam milk and are required for transfer of protection.

    (A) Numbers of Thy1.1+CD4+ and Thy1.1+CD4+ST2+ T cells in milk pellet from the stomach of Thy1.2 pups at day 10 after birth. (B) Three-day-old NvM pups were fostered on WT NvM/NbM or ilckcreIL-4Rα−/lox dams. Pups were infected when 14 days old with 250 × Nb L3 and euthanized at day 5 PI. Offspring intestinal worm burden was analyzed, and IL-13 secretion by anti-CD3–restimulated splenocytes was quantified at day 5 PI. All data are representative of a minimum of two experimental repeats. *P < 0.05 and **P < 0.01.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/5/eaav3058/DC1

    Fig. S1. Offspring acquire, via nursing, a population of maternally derived CD4 T cells with a heightened TH2 responsiveness following Nb infection.

    Fig. S2. Offspring nursed on Hp-infected mothers do not demonstrate maternal cell transfer.

    Fig. S3. Allogeneic NbM offspring have raised numbers of maternally derived lung CD4+ T cells following Nb infection.

    Fig. S4. Offspring acquire, via nursing, persistent protection from Nb related to raised TH2 CD4+ T cell responses following Nb infection in an allogeneic setting.

  • Supplementary Materials

    This PDF file includes:

    • Fig. S1. Offspring acquire, via nursing, a population of maternally derived CD4 T cells with a heightened TH2 responsiveness following Nb infection.
    • Fig. S2. Offspring nursed on Hp-infected mothers do not demonstrate maternal cell transfer.
    • Fig. S3. Allogeneic NbM offspring have raised numbers of maternally derived lung CD4+ T cells following Nb infection.
    • Fig. S4. Offspring acquire, via nursing, persistent protection from Nb related to raised TH2 CD4+ T cell responses following Nb infection in an allogeneic setting.

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