Abstract
Efficient immune defenses are facilitated by the organized microarchitecture of lymphoid organs, and this organization is regulated by the compartmentalized expression of lymphoid tissue chemokines. Mouse cytomegalovirus (MCMV) infection induces significant remodeling of splenic microarchitecture, including loss of marginal zone macrophage populations and dissolution of T and B cell compartmentalization. MCMV preferentially infected the splenic stroma, targeting endothelial cells (EC) as revealed using MCMV-expressing green fluorescent protein. MCMV infection caused a specific, but transient transcriptional suppression of secondary lymphoid chemokine (CCL21). The loss of CCL21 was associated with the failure of T lymphocytes to locate within the T cell zone, although trafficking to the spleen was unaltered. Expression of CCL21 in lymphotoxin (LT)-α–deficient mice is dramatically reduced, however MCMV infection further reduced CCL21 levels, suggesting that viral modulation of CCL21 was independent of LTα signaling. Activation of LTβ-receptor signaling with an agonistic antibody partially restored CCL21 mRNA expression and redirected transferred T cells to the splenic T cell zone in MCMV-infected mice. These results indicate that virus-induced alterations in lymphoid tissues can occur through an LT-independent modulation of chemokine transcription, and targeting of the LT cytokine system can counteract lymphoid tissue remodeling by MCMV.
Highlights
The microarchitecture of secondary lymphoid organs, like the spleen, facilitates effective communication between antigen-presenting cells and T lymphocytes to mount protective immunity to pathogens
After Mouse cytomegalovirus (MCMV) infection, an abnormally broad pattern of gp38 staining was observed throughout the white pulp, which in uninfected mice is restricted to the periarteriolar lymphoid sheath (PALS) (Figure 1A)
B6 mice are relatively resistant to MCMV infection, primarily through the action of the cmv1 dominant-acting resistance gene encoding the Ly49H-activating receptor expressed on a subset of natural killer (NK) cells, which help to control viral replication in the spleen [17,24,25]
Summary
The microarchitecture of secondary lymphoid organs, like the spleen, facilitates effective communication between antigen-presenting cells and T lymphocytes to mount protective immunity to pathogens. The localization and subsequent organization of T and B lymphocytes to the white pulp is regulated through their interactions with unique populations of chemokine-producing stromal cells [2]. Naive T lymphocytes express high levels of the chemokine receptor CCR7, and upon entering the spleen they migrate toward, and congregate upon, stromal cells that produce the secondary lymphoid tissue chemokines CCL21 (SLC/6Ckine/Exodus-2/TCA4;) and CCL19 (ELC/MIP3b) [3,4]. CCL21-ser regulation of cellular trafficking seems to be due to its high expression levels compared with CCL21-leu(b) in lymphoid tissues, and not a functional difference between these two isoforms in mediating cellular chemotaxis [7]. All mature B cells express the chemokine receptor CXCR5, and migrate in response to the production of B lymphoid chemoattractant CXCL13 by radio-resistant stromal cells present in the B cell follicle [8,9]
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