Pathogen-imposed skewing of mouse chemokine and cytokine expression at the infected tissue site
Shoshana D. Katzman, Deborah J. Fowell
Shoshana D. Katzman, Deborah J. Fowell
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):801-811. https://doi.org/10.1172/JCI33174.
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Research Article Immunology

Pathogen-imposed skewing of mouse chemokine and cytokine expression at the infected tissue site

Abstract

Compartmentalization of immunity ensures tight regulation of T cell activation in the LN and precise effector T cell delivery to inflamed sites. Herein we show that the tissue-specific accumulation of effector T cells can be subverted by a pathogen at the infection site. Using the Leishmania major mouse model of dermal infection, we observed a restricted chemokine profile at the infection site, i.e., the expression of Th2 cell–attracting CCL7 but not of Th1 cell–attracting chemokines. Consistent with these chemokine expression data, recruitment of cytokine-producing T cells to the infection site was also selective. Both IL-4– and IFN-γ–producing effector T cells homed to inflamed OVA/CFA-immunized dermis, but only IL-4–producing cells homed to L. major–infected dermis. The narrowing of the cytokine repertoire at the site of infection with L. major was driven, in part, by pathogen-induced CCL7. Inflammatory signals failed to disrupt the early restrictive L. major infection site, which suggests that L. major dominantly modifies the local milieu. We have highlighted an emerging principle in pathogen-host interactions: that the cytokine repertoire at the infection site and the LN draining the infection site can be different because of the ability of the pathogen to modify the chemokine profile at the infection site. Thus, pathogens may edit the LN cytokine repertoire through differential recruitment of cytokine-producing cells.

Authors

Shoshana D. Katzman, Deborah J. Fowell

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Figure 5

Restricted cytokine responses at the site of early L. major infection.

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Restricted cytokine responses at the site of early L. major infection. ...
(A) Ear and dLN cell suspensions from mice 2 weeks after infection with L. major were stimulated for 6 hours with SLA in vitro, and cytokine-producing cells were determined by ELISPOT. Each bar represents a pool of 4 infected mice. *P values for the increase in the ratio of IL-4/IFN-γ in the infected ear compared with the dLN as determined by Mann-Whitney U test: P = 0.002 BALB/c mice, n = 12 experiments; P = 0.01 for B10.D2 mice, n = 6 experiments; and P = 0.002 for C57BL/6 mice, n = 6 experiments. Right: Parasite load in ear 2 weeks after infection. (B) CFSE-labeled LN cells from BALB/c mice were cultured for 72 hours with SLA and cytokines measured by intracellular cytokine staining. Numbers represent the percentage of L. major–specific cytokine-secreting cells. (C) Total CD4+ T cell numbers and L. major–specific cytokine-producing spots in the ear of BALB/c mice 2 weeks after L. major infection. (D) Ex vivo production of IL-4 and IFN-γ measured by cytokine capture assay, 2 weeks after L. major infection of BALB 4get mice. Plots gated on CD4+ T cells. The numbers in quadrants represent the percentage and numbers (in parentheses) of CD4+ T cells per ear. Background staining was 0.01%–0.2%. Data are representative of 3 separate experiments. (E) BALB/c mice were immunized with SLA in the ear dermis, and 2 weeks later cytokine production was assayed as in A. Data are from 1 of 3 comparable experiments. (F) BALB/c mice were injected with OVA/CFA or L. major. Antigen-specific cytokines were assayed as in A. Results are representative of at least 3 individual experiments. Results were similar in L. major–infected C57BL/6 mice. (G) BALB/c LACK-specific TCR Tg+ mice were infected with L. major, and cytokines were analyzed 2 weeks later as in A. *P ≤ 0.05 for the difference in IFN-γ–producing cells in the ear and the dLN as determined by Student’s t test. (H) Ratio of IL-4/IFN-γ–producing cells in BALB/c and C57BL/6 mice from the dLN and ear and determined as in A. Data are the mean ± SD of 4 experiments.