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. 2006 Apr 17;203(4):933-40.
doi: 10.1084/jem.20060045. Epub 2006 Mar 20.

Lymphocytes Are Detrimental During the Early Innate Immune Response Against Listeria Monocytogenes

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Free PMC article

Lymphocytes Are Detrimental During the Early Innate Immune Response Against Listeria Monocytogenes

Javier A Carrero et al. J Exp Med. .
Free PMC article

Abstract

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor-deficient (IFN-alphabetaR(-/-)) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-alphabetaR(+/+). The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection.

Figures

Figure 1.
Figure 1.
SCID mice are more resistant to L. monocytogenes growth than wild-type C.B-17 mice. (A) Mice were infected with 107 CFU and colony counts were determined after 6 h. (B) Mice were infected with 5 × 104 CFU and colony counts were determined at day 4 after infection. (C) SCID and C.B-17 mice were infected with the indicated doses, and spleen and liver colony counts were determined at day 4 of infection. All bars represent the mean ± SEM for 5–16 mice per group. (D) IL-6, (E) TNF-α, (F) IFN-γ, (G) MCP-1, and (H) IL-12 were determined for C.B-17 and SCID mice infected with 5 × 104 CFU at the indicated times after infection.
Figure 2.
Figure 2.
Engraftment of lymphocytes into RAG2−/− mice increases susceptibility to listeriosis. Lethally irradiated RAG2−/− recipients were engrafted with the indicated bone marrow donors (chimeras) for 70–80 d. All mice were infected with 2.5 × 104 L. monocytogenes. Colony counts were determined at (A and B) days 2 and (C and D) 4 after infection. For all graphs: 129SvEv, 129/SvEv→RAG2−/−; IFNAR, IFN-αβR−/−→RAG2−/−; mixed, a five to one RAG2−/− to IFN-αβR−/− mix→RAG2−/−; RAG, untransplanted RAG2−/− mice. All bars represent the mean ± SEM for four to nine mice per group.
Figure 3.
Figure 3.
Increased inflammatory cytokine responses in 129/SvEv engrafted RAG2−/− mice. Mice were transplanted and infected i.p. with 2.5 × 104 L. monocytogenes. Serum levels of (A) IL-6, (B) TNF-α, (C) MCP-1, (D) IFN-γ, and (E) IL-12p70 were determined at days 2 and 4 after infection as indicated on the graphs. For all graphs: 129/SvEv, 129→RAG2−/−; IFNAR, IFN-αβR−/−→RAG2−/−; mixed, a five to one RAG2−/− to IFN-αβR−/−→RAG2−/−; RAG, untransplanted RAG2−/− mice. All bars indicate the mean ± SEM for 4–10 mice per group.
Figure 4.
Figure 4.
Histological analysis of bone marrow chimeras infected with L. monocytogenes. Mice were chimerized as described in the legend to Fig. 2. Spleens from mice infected with 2.5 × 104 CFU of L. monocytogenes EGD strain were stained as described previously by (A, C, and E) H&E or (B, D, and F) TUNEL. Results are shown for (A and B) 129/SvEv→RAG2−/− chimeras, (C and D) IFN-αβR−/−→RAG2−/− chimeras, or untransplanted RAG2−/− mice. Of note is the dramatic lymphocyte apoptosis found only in 129/SvEV chimeras but not IFN-αβR−/− chimeras. Bar, 50 μM.
Figure 5.
Figure 5.
Effect of poly(I:C) on listeriosis in SCID mice. (A and B) C.B-17 or SCID mice were left untreated or were treated with 250 (C.B-17) or 500 μg (SCID) poly(I:C) i.v. and then infected with 5 × 104 L. monocytogenes strain EGD i.p. (A) Spleen and (B) liver colony counts were determined at day 3 after infection. (C) SCID and C.B-17 mice were injected with the indicated doses of poly(I:C) i.v. for 6 h, and type I IFN levels were measured in the serum. Bars represent the mean ± SEM for 8–14 mice per group. (D and E) SCID and (F and G) SCID mice treated with 500 μg poly(I:C) were infected for 3 d with 5 × 104 L. monocytogenes EGD strain, and spleen sections were stained by (D and F) H&E or (E and G) by TUNEL. Yellow bars, 50 μm. *, P = 0.0002; **, P < 0.0001 by Mann-Whitney U test.
Figure 6.
Figure 6.
Increased resistance to listeriosis in IL-10−/− mice. (A and B) C57BL/6J and IL-10−/− mice were infected with 105 L. monocytogenes and colony counts were determined for the (A) spleen and (B) liver at the indicated days. Levels of (C) IL-10 and (D) IFN-γ were determined for cell-free spleen homogenates of uninfected or infected 129/SvEv, IFN-αβR−/−, or RAG2−/− mice as indicated on the graph. All bars represent the mean ± SEM for at least 4–10 mice per group. *, P = 0.0104, Mann-Whitney U test. Serial sections were made from the spleens of (E and G) C57/BL6J or (F and H) IL-10−/− mice and stained by (E and F) H&E or (G and H) TUNEL. Yellow bars, 50 μm.

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