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 6

Site-specific and CCL7-dependent accumulation of distinct cytokine-producing effector T cells.

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Site-specific and CCL7-dependent accumulation of distinct cytokine-produ...
(A) BALB/c mice were infected with L. major in the right ear and injected with CFA in the left ear. L. major–draining LN and L. major or CFA ear cell suspensions were stimulated 2 weeks later with SLA for cytokine ELISPOT. Data are representative of 3 comparable experiments. P value by Mann-Whitney U test. Similar results were observed in C57BL/6 mice. (B) APCs from uninfected LN (left) and from ear tissue of BALB/c mice 2 weeks after infection with L. major (right) were used to restimulate D011.10-primed Th1 and Th2 effector cells, and cytokines were measured by antigen-specific ELISPOT with 5 μM pOVA 323-339 for 6 hours (cytokine production from T cells alone and APCs alone subtracted). (C) Restimulation of in vitro primed effectors with APC from ears of 2-week L. major–infected or CFA-immunized BALB/c mice. APC numbers were normalized to IAd+ cells for B and C. Data are representative of 3 comparable experiments. (D) An anti-CCL7 polyclonal or control Ab (250 μg/ear) was injected directly into L. major–infected dermis of BALB/c 4 get mice 2 weeks after infection. Three days after antibody treatment, cells were isolated from the dLN and the ear and restimulated with SLA. The number of IL-4–producing cells was then determined by ELISPOT. Cytokine-producing cells/106 for LN or per ear; n = 6 mice per group. (E) Number of eGFPhi CD4+ T cells in the dermis after Ab treatment of L. major–infected ears by FACS. Data in D and E are representative of 2 comparable experiments.