Specific Remodeling of Splenic Architecture by Cytomegalovirus

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. The architecture of the spleen and lymph nodes is organized into discrete compartments that promote the immune system's ability to capture pathogens and mount protective defenses. The white blood cells that fill these compartments are positioned in discrete regions by chemoattractants produced by the cells that form the architecture of the spleen (stroma). The white blood cells must be positioned to interact with each other to mount effective host defense. Benedict and colleagues demonstrate that cytomegalovirus, a β herpesvirus, can remodel the architecture of the spleen by specifically inhibiting a key chemoattractant produced by the stromal cells, the chemokine CCL21. This action by the virus impedes efficient contact between cells by altering the movement of T lymphocytes to their correct position within the spleen. However, as a counter strategy, activating the lymphotoxin-β receptor pathway, a cytokine known to control the embryonic development of lymphoid organs, partially restored CCL21 and the ability of T lymphocytes to find their correct position. Thus, infection with this herpesvirus selectively remodels the structure of lymphoid tissues perhaps aiding in the formation of a portal though host defenses.