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Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period.

Torow N, Yu K, Hassani K, Freitag J, Schulz O, Basic M, Brennecke A, Sparwasser T, Wagner N, Bleich A, Lochner M, Weiss S, Förster R, Pabst O, Hornef MW - Nat Commun (2015)

Bottom Line: Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile.Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption.Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany [2] Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany.

ABSTRACT
Priming of the mucosal immune system during the postnatal period substantially influences host-microbial interaction and susceptibility to immune-mediated diseases in adult life. The underlying mechanisms are ill defined. Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile. T-cell recruitment is independent of microbial colonization and innate or adaptive immune stimulation but requires β7 integrin expression. Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption. Maternal SIgA and regulatory T cells act in concert to prevent immune stimulation and maintain the immature phenotype of CD4 T cells in the postnatal intestine during homeostasis. Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.

No MeSH data available.


Related in: MedlinePlus

Mechanisms that maintain immaturity of intestinal CD4 T cells during the homeostatic postnatal period.(a) Percentage of CD44hi CD4 T cells in the SI of 11-day-old B-cell-sufficient (μMT+/− or μMT+/+) (left panel) and IgA-sufficient (pIgR+/− or pIgR+/+)(right panel) neonates fed by B-cell or IgA-sufficient (wt mother) or deficient (μMT−/− or pIgR−/− mother) dams. (μMt: n=4 litters from four experiments; pIgR: n=2 litters from two experiments, mean; unpaired Student's t-test, **P<0.01, ***P<0.001). (b) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII cells together with neonatal or adult PP cells for 3 days at the indicated ratio (ratio PP:OTII; n=4 technical replicates, representative of five similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni's post test, ***P<0.001). (c) Comparative proliferation assay culturing OVA-loaded BMDCs, and eFluor670-labelled OTII T lymphocytes together with FACS-sorted subgroups of neonatal PP cells for 3 days at the ratio of 4:1 (PP:OTII: B and T cells) or 2:1 (PP:OTII: stroma and rest). (n=3–4 technical replicates, representative of four similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001). (d) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII T lymphocytes together with FACS sorted neonatal regulatory T cells (TReg, from Foxp3 reporter mice) for 3 days at the ratio of 4:1 (ratio PP:OTII). (n=2 replicates from two experiments with TRegs pooled from 20 and 8 neonates per experiment, respectively, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001, NS, not significant). (e) Percentage of CD44hi cells among CD4 T lymphocytes (using non-transgenic littermate controls as a reference gate) in the SI of 11-day-old DEREG mice and non-transgenic littermate controls all treated with DT on days 1/2/5/6 (n=5 litters from five experiments, mean; unpaired Student's t-test, **P<0.01.
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f5: Mechanisms that maintain immaturity of intestinal CD4 T cells during the homeostatic postnatal period.(a) Percentage of CD44hi CD4 T cells in the SI of 11-day-old B-cell-sufficient (μMT+/− or μMT+/+) (left panel) and IgA-sufficient (pIgR+/− or pIgR+/+)(right panel) neonates fed by B-cell or IgA-sufficient (wt mother) or deficient (μMT−/− or pIgR−/− mother) dams. (μMt: n=4 litters from four experiments; pIgR: n=2 litters from two experiments, mean; unpaired Student's t-test, **P<0.01, ***P<0.001). (b) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII cells together with neonatal or adult PP cells for 3 days at the indicated ratio (ratio PP:OTII; n=4 technical replicates, representative of five similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni's post test, ***P<0.001). (c) Comparative proliferation assay culturing OVA-loaded BMDCs, and eFluor670-labelled OTII T lymphocytes together with FACS-sorted subgroups of neonatal PP cells for 3 days at the ratio of 4:1 (PP:OTII: B and T cells) or 2:1 (PP:OTII: stroma and rest). (n=3–4 technical replicates, representative of four similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001). (d) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII T lymphocytes together with FACS sorted neonatal regulatory T cells (TReg, from Foxp3 reporter mice) for 3 days at the ratio of 4:1 (ratio PP:OTII). (n=2 replicates from two experiments with TRegs pooled from 20 and 8 neonates per experiment, respectively, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001, NS, not significant). (e) Percentage of CD44hi cells among CD4 T lymphocytes (using non-transgenic littermate controls as a reference gate) in the SI of 11-day-old DEREG mice and non-transgenic littermate controls all treated with DT on days 1/2/5/6 (n=5 litters from five experiments, mean; unpaired Student's t-test, **P<0.01.

Mentions: We next aimed at identifying mechanisms that actively suppress CD4+ T-cell maturation in the neonate intestine under homeostatic conditions. First, we examined antigen uptake by neonatal antigen-presenting cells, since antigen presentation is a prerequisite for T-cell activation. MHCII+CD11b+ antigen-presenting cells were present in the neonate intestine (Fig. 1b). Also, orally administered fluorophore-conjugated antigen was rapidly (<4 h) delivered from the intestinal lumen and internalized by MHCII+ myeloid cells of the neonatal small intestinal mucosa (Supplementary Fig. 4a). Since antigen uptake and presentation by antigen-presenting cells seemed unaffected in neonates, we next sought to test whether antigen sequestration by maternal immunoglobulins that are abundantly present in breast milk might contribute to sustained naïveté of neonatal small intestinal CD4+ T cells. We therefore crossed B-cell-deficient homozygous μMT−/− dams and μMT+/+ sires. The B-cell-proficient heterozygous (μMT+/−) offspring exhibit a normal B-cell compartment but lack exposure to maternal breast milk-transferred immunoglobulins. Indeed, heterozygous μMT neonates from homozygous B-cell-deficient μMT dams harboured enhanced numbers of CD44hiCD62Llow expressing intestinal CD4+ T cells in Fig. 5a and Supplementary Fig. 4b,c. We additionally analysed heterozygous neonates from pIgR-deficient dams that produce immunoglobulins but are unable to secrete polymeric immunoglobulins into the breast milk39. Again, neonates from these animals exhibited an enhanced fraction of CD44hi expressing intestinal CD4+ T cells (Fig. 5a and Supplementary Fig. 4c). This suggests that antibodies in breast milk, in particular SIgA, restrict the level of exposure to antigens and contribute to the maintenance of immature intestinal CD4+ T cells in the neonate host.


Active suppression of intestinal CD4(+)TCRαβ(+) T-lymphocyte maturation during the postnatal period.

Torow N, Yu K, Hassani K, Freitag J, Schulz O, Basic M, Brennecke A, Sparwasser T, Wagner N, Bleich A, Lochner M, Weiss S, Förster R, Pabst O, Hornef MW - Nat Commun (2015)

Mechanisms that maintain immaturity of intestinal CD4 T cells during the homeostatic postnatal period.(a) Percentage of CD44hi CD4 T cells in the SI of 11-day-old B-cell-sufficient (μMT+/− or μMT+/+) (left panel) and IgA-sufficient (pIgR+/− or pIgR+/+)(right panel) neonates fed by B-cell or IgA-sufficient (wt mother) or deficient (μMT−/− or pIgR−/− mother) dams. (μMt: n=4 litters from four experiments; pIgR: n=2 litters from two experiments, mean; unpaired Student's t-test, **P<0.01, ***P<0.001). (b) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII cells together with neonatal or adult PP cells for 3 days at the indicated ratio (ratio PP:OTII; n=4 technical replicates, representative of five similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni's post test, ***P<0.001). (c) Comparative proliferation assay culturing OVA-loaded BMDCs, and eFluor670-labelled OTII T lymphocytes together with FACS-sorted subgroups of neonatal PP cells for 3 days at the ratio of 4:1 (PP:OTII: B and T cells) or 2:1 (PP:OTII: stroma and rest). (n=3–4 technical replicates, representative of four similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001). (d) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII T lymphocytes together with FACS sorted neonatal regulatory T cells (TReg, from Foxp3 reporter mice) for 3 days at the ratio of 4:1 (ratio PP:OTII). (n=2 replicates from two experiments with TRegs pooled from 20 and 8 neonates per experiment, respectively, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001, NS, not significant). (e) Percentage of CD44hi cells among CD4 T lymphocytes (using non-transgenic littermate controls as a reference gate) in the SI of 11-day-old DEREG mice and non-transgenic littermate controls all treated with DT on days 1/2/5/6 (n=5 litters from five experiments, mean; unpaired Student's t-test, **P<0.01.
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f5: Mechanisms that maintain immaturity of intestinal CD4 T cells during the homeostatic postnatal period.(a) Percentage of CD44hi CD4 T cells in the SI of 11-day-old B-cell-sufficient (μMT+/− or μMT+/+) (left panel) and IgA-sufficient (pIgR+/− or pIgR+/+)(right panel) neonates fed by B-cell or IgA-sufficient (wt mother) or deficient (μMT−/− or pIgR−/− mother) dams. (μMt: n=4 litters from four experiments; pIgR: n=2 litters from two experiments, mean; unpaired Student's t-test, **P<0.01, ***P<0.001). (b) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII cells together with neonatal or adult PP cells for 3 days at the indicated ratio (ratio PP:OTII; n=4 technical replicates, representative of five similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni's post test, ***P<0.001). (c) Comparative proliferation assay culturing OVA-loaded BMDCs, and eFluor670-labelled OTII T lymphocytes together with FACS-sorted subgroups of neonatal PP cells for 3 days at the ratio of 4:1 (PP:OTII: B and T cells) or 2:1 (PP:OTII: stroma and rest). (n=3–4 technical replicates, representative of four similar independent experiments, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001). (d) Comparative proliferation assay culturing OVA-loaded BMDCs, eFluor670-labelled OTII T lymphocytes together with FACS sorted neonatal regulatory T cells (TReg, from Foxp3 reporter mice) for 3 days at the ratio of 4:1 (ratio PP:OTII). (n=2 replicates from two experiments with TRegs pooled from 20 and 8 neonates per experiment, respectively, mean±s.d.; one-way ANOVA, Bonferroni 's post test, ***P<0.001, NS, not significant). (e) Percentage of CD44hi cells among CD4 T lymphocytes (using non-transgenic littermate controls as a reference gate) in the SI of 11-day-old DEREG mice and non-transgenic littermate controls all treated with DT on days 1/2/5/6 (n=5 litters from five experiments, mean; unpaired Student's t-test, **P<0.01.
Mentions: We next aimed at identifying mechanisms that actively suppress CD4+ T-cell maturation in the neonate intestine under homeostatic conditions. First, we examined antigen uptake by neonatal antigen-presenting cells, since antigen presentation is a prerequisite for T-cell activation. MHCII+CD11b+ antigen-presenting cells were present in the neonate intestine (Fig. 1b). Also, orally administered fluorophore-conjugated antigen was rapidly (<4 h) delivered from the intestinal lumen and internalized by MHCII+ myeloid cells of the neonatal small intestinal mucosa (Supplementary Fig. 4a). Since antigen uptake and presentation by antigen-presenting cells seemed unaffected in neonates, we next sought to test whether antigen sequestration by maternal immunoglobulins that are abundantly present in breast milk might contribute to sustained naïveté of neonatal small intestinal CD4+ T cells. We therefore crossed B-cell-deficient homozygous μMT−/− dams and μMT+/+ sires. The B-cell-proficient heterozygous (μMT+/−) offspring exhibit a normal B-cell compartment but lack exposure to maternal breast milk-transferred immunoglobulins. Indeed, heterozygous μMT neonates from homozygous B-cell-deficient μMT dams harboured enhanced numbers of CD44hiCD62Llow expressing intestinal CD4+ T cells in Fig. 5a and Supplementary Fig. 4b,c. We additionally analysed heterozygous neonates from pIgR-deficient dams that produce immunoglobulins but are unable to secrete polymeric immunoglobulins into the breast milk39. Again, neonates from these animals exhibited an enhanced fraction of CD44hi expressing intestinal CD4+ T cells (Fig. 5a and Supplementary Fig. 4c). This suggests that antibodies in breast milk, in particular SIgA, restrict the level of exposure to antigens and contribute to the maintenance of immature intestinal CD4+ T cells in the neonate host.

Bottom Line: Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile.Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption.Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany [2] Institute of Medical Microbiology, RWTH University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany.

ABSTRACT
Priming of the mucosal immune system during the postnatal period substantially influences host-microbial interaction and susceptibility to immune-mediated diseases in adult life. The underlying mechanisms are ill defined. Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile. T-cell recruitment is independent of microbial colonization and innate or adaptive immune stimulation but requires β7 integrin expression. Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption. Maternal SIgA and regulatory T cells act in concert to prevent immune stimulation and maintain the immature phenotype of CD4 T cells in the postnatal intestine during homeostasis. Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.

No MeSH data available.


Related in: MedlinePlus