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Hypertrophy of infected Peyer's patches arises from global, interferon-receptor, and CD69-independent shutdown of lymphocyte egress.

Schulz O, Ugur M, Friedrichsen M, Radulovic K, Niess JH, Jalkanen S, Krueger A, Pabst O - Mucosal Immunol (2013)

Bottom Line: Intriguingly, the exact nature of these changes remains undefined to date.Surprisingly, infection-induced lymphocyte sequestration did not require previously proposed mediators of lymphoid organ shutdown including type I interferon receptor and CD69.In contrast, following T-cell receptor-mediated priming, CD69 was essential to selectively block CD4(+) effector T-cell egress.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Lymphoid organ hypertrophy is a hallmark of localized infection. During the inflammatory response, massive changes in lymphocyte recirculation and turnover boost lymphoid organ cellularity. Intriguingly, the exact nature of these changes remains undefined to date. Here, we report that hypertrophy of Salmonella-infected Peyer's patches (PPs) ensues from a global "shutdown" of lymphocyte egress, which traps recirculating lymphocytes in PPs. Surprisingly, infection-induced lymphocyte sequestration did not require previously proposed mediators of lymphoid organ shutdown including type I interferon receptor and CD69. In contrast, following T-cell receptor-mediated priming, CD69 was essential to selectively block CD4(+) effector T-cell egress. Our findings segregate two distinct lymphocyte sequestration mechanisms, which differentially rely on intrinsic modulation of lymphocyte egress capacity and inflammation-induced changes in the lymphoid organ environment.

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Lymphocyte composition and turnover during infection-induced Peyer's patch (PPs) hypertrophy. (a) Cell counts in non-infected (d0) or Salmonella-infected (d7) PPs. Median+inter-quartile range (IQR) of 61 and 89 individual PPs from 10 to 12 mice per group, four independent experiments. (b) PP cell composition, determined using flow cytometry. Mean+s.d. of individual PPs from total 45 mice, eight independent experiments. (c) 5-bromo-2-deoxyuridine (BrdU) incorporation into PP cells during infection. Non-infected (d0) or infected (d7) mice were given BrdU in the drinking water for 7 days. One of two independent experiments, mean+s.d. of four mice per group, PP pools analyzed. (d) Lymphocyte entry into infected PPs. A total of 107 cells were transferred to non-infected or infected congenic recipients. PPs were analyzed 2 or 4 h later. Individual PPs from nine (d0), six (d1), or three (d3, d7) mice per group, four independent experiments. Numbers normalized to average number of transferred cells in non-infected PPs. One-way analysis of variance (ANOVA) with Tukey's multiple comparison test.
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fig1: Lymphocyte composition and turnover during infection-induced Peyer's patch (PPs) hypertrophy. (a) Cell counts in non-infected (d0) or Salmonella-infected (d7) PPs. Median+inter-quartile range (IQR) of 61 and 89 individual PPs from 10 to 12 mice per group, four independent experiments. (b) PP cell composition, determined using flow cytometry. Mean+s.d. of individual PPs from total 45 mice, eight independent experiments. (c) 5-bromo-2-deoxyuridine (BrdU) incorporation into PP cells during infection. Non-infected (d0) or infected (d7) mice were given BrdU in the drinking water for 7 days. One of two independent experiments, mean+s.d. of four mice per group, PP pools analyzed. (d) Lymphocyte entry into infected PPs. A total of 107 cells were transferred to non-infected or infected congenic recipients. PPs were analyzed 2 or 4 h later. Individual PPs from nine (d0), six (d1), or three (d3, d7) mice per group, four independent experiments. Numbers normalized to average number of transferred cells in non-infected PPs. One-way analysis of variance (ANOVA) with Tukey's multiple comparison test.

Mentions: Intestinal PPs are secondary lymphoid organs that participate in homeostatic lymphocyte recirculation, release naive lymphocytes into efferent lymph in an S1PR1-dependent manner,19 and become hypertrophic during infection. The experimental model we used to investigate PP hypertrophy is an oral infection with an attenuated strain of Salmonella enterica Serovar Typhimurium (SL1344ΔaroA). This strain enters PPs, established infection and spreads to mesenteric lymph nodes (mLNs), liver, and spleen.33 Seven days after infection, PPs had visibly enlarged in size and contained on average 1.5-fold more cells than PPs from non-infected control mice (Figure 1a). The lymphocyte composition in PPs did not change substantially during the first week of infection (Figure 1b), suggesting that PP hypertrophy does not result from an increase in frequency of a particular subpopulation but from the accumulation of all major PP cell types. Consistently, PP lymphocyte populations did not strongly incorporate the thymidine analog 5-bromo-2-deoxyuridine throughout the infection period, indicating that cell proliferation did not substantially contribute to lymphocyte accumulation in infected PPs (Figure 1c). To address whether lymphocyte entry into infected PPs was increased and contributed to PP hypertrophy, we performed short-term adoptive transfer experiments. Congenically marked lymphocytes were transferred intravenously to non-infected or infected recipients on days 1, 3, or 7 of infection. The number of transferred cells in PPs was determined at 2 or 4 h post transfer. At these early time points, the number of transferred cells monitors entry and is not affected by egress.34 Entry of transferred cells into infected PPs was not significantly enhanced in infected compared with non-infected recipients (Figure 1d), suggesting that changes in lymphocyte recruitment are not a major contributor to lymphocyte accumulation in infected PPs.


Hypertrophy of infected Peyer's patches arises from global, interferon-receptor, and CD69-independent shutdown of lymphocyte egress.

Schulz O, Ugur M, Friedrichsen M, Radulovic K, Niess JH, Jalkanen S, Krueger A, Pabst O - Mucosal Immunol (2013)

Lymphocyte composition and turnover during infection-induced Peyer's patch (PPs) hypertrophy. (a) Cell counts in non-infected (d0) or Salmonella-infected (d7) PPs. Median+inter-quartile range (IQR) of 61 and 89 individual PPs from 10 to 12 mice per group, four independent experiments. (b) PP cell composition, determined using flow cytometry. Mean+s.d. of individual PPs from total 45 mice, eight independent experiments. (c) 5-bromo-2-deoxyuridine (BrdU) incorporation into PP cells during infection. Non-infected (d0) or infected (d7) mice were given BrdU in the drinking water for 7 days. One of two independent experiments, mean+s.d. of four mice per group, PP pools analyzed. (d) Lymphocyte entry into infected PPs. A total of 107 cells were transferred to non-infected or infected congenic recipients. PPs were analyzed 2 or 4 h later. Individual PPs from nine (d0), six (d1), or three (d3, d7) mice per group, four independent experiments. Numbers normalized to average number of transferred cells in non-infected PPs. One-way analysis of variance (ANOVA) with Tukey's multiple comparison test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4060605&req=5

fig1: Lymphocyte composition and turnover during infection-induced Peyer's patch (PPs) hypertrophy. (a) Cell counts in non-infected (d0) or Salmonella-infected (d7) PPs. Median+inter-quartile range (IQR) of 61 and 89 individual PPs from 10 to 12 mice per group, four independent experiments. (b) PP cell composition, determined using flow cytometry. Mean+s.d. of individual PPs from total 45 mice, eight independent experiments. (c) 5-bromo-2-deoxyuridine (BrdU) incorporation into PP cells during infection. Non-infected (d0) or infected (d7) mice were given BrdU in the drinking water for 7 days. One of two independent experiments, mean+s.d. of four mice per group, PP pools analyzed. (d) Lymphocyte entry into infected PPs. A total of 107 cells were transferred to non-infected or infected congenic recipients. PPs were analyzed 2 or 4 h later. Individual PPs from nine (d0), six (d1), or three (d3, d7) mice per group, four independent experiments. Numbers normalized to average number of transferred cells in non-infected PPs. One-way analysis of variance (ANOVA) with Tukey's multiple comparison test.
Mentions: Intestinal PPs are secondary lymphoid organs that participate in homeostatic lymphocyte recirculation, release naive lymphocytes into efferent lymph in an S1PR1-dependent manner,19 and become hypertrophic during infection. The experimental model we used to investigate PP hypertrophy is an oral infection with an attenuated strain of Salmonella enterica Serovar Typhimurium (SL1344ΔaroA). This strain enters PPs, established infection and spreads to mesenteric lymph nodes (mLNs), liver, and spleen.33 Seven days after infection, PPs had visibly enlarged in size and contained on average 1.5-fold more cells than PPs from non-infected control mice (Figure 1a). The lymphocyte composition in PPs did not change substantially during the first week of infection (Figure 1b), suggesting that PP hypertrophy does not result from an increase in frequency of a particular subpopulation but from the accumulation of all major PP cell types. Consistently, PP lymphocyte populations did not strongly incorporate the thymidine analog 5-bromo-2-deoxyuridine throughout the infection period, indicating that cell proliferation did not substantially contribute to lymphocyte accumulation in infected PPs (Figure 1c). To address whether lymphocyte entry into infected PPs was increased and contributed to PP hypertrophy, we performed short-term adoptive transfer experiments. Congenically marked lymphocytes were transferred intravenously to non-infected or infected recipients on days 1, 3, or 7 of infection. The number of transferred cells in PPs was determined at 2 or 4 h post transfer. At these early time points, the number of transferred cells monitors entry and is not affected by egress.34 Entry of transferred cells into infected PPs was not significantly enhanced in infected compared with non-infected recipients (Figure 1d), suggesting that changes in lymphocyte recruitment are not a major contributor to lymphocyte accumulation in infected PPs.

Bottom Line: Intriguingly, the exact nature of these changes remains undefined to date.Surprisingly, infection-induced lymphocyte sequestration did not require previously proposed mediators of lymphoid organ shutdown including type I interferon receptor and CD69.In contrast, following T-cell receptor-mediated priming, CD69 was essential to selectively block CD4(+) effector T-cell egress.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.

ABSTRACT
Lymphoid organ hypertrophy is a hallmark of localized infection. During the inflammatory response, massive changes in lymphocyte recirculation and turnover boost lymphoid organ cellularity. Intriguingly, the exact nature of these changes remains undefined to date. Here, we report that hypertrophy of Salmonella-infected Peyer's patches (PPs) ensues from a global "shutdown" of lymphocyte egress, which traps recirculating lymphocytes in PPs. Surprisingly, infection-induced lymphocyte sequestration did not require previously proposed mediators of lymphoid organ shutdown including type I interferon receptor and CD69. In contrast, following T-cell receptor-mediated priming, CD69 was essential to selectively block CD4(+) effector T-cell egress. Our findings segregate two distinct lymphocyte sequestration mechanisms, which differentially rely on intrinsic modulation of lymphocyte egress capacity and inflammation-induced changes in the lymphoid organ environment.

Show MeSH
Related in: MedlinePlus