Abstract
Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)βR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1β2/LTβR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis.
Highlights
To dissect the dynamics of lymphatic vessel expansion in the context of ectopic lymphoneogenesis, we used a model of tertiary lymphoid structure (TLS) formation in the salivary glands, where the single administration of a replicationdeficient adenovirus via retrograde cannulation of submandibular glands is sufficient to induce focal aggregate formation as observed in human Sjogren’s syndrome [28]
This model is characterized by expansion of lymphoid aggregates, T/B cell segregation, and lymphoid chemokine expression, which reaches a peak around day 15 p.c. and undergoes resolution with complete lymphocyte clearance by day 30 p.c. (Supplemental Fig. 1A)
Flow cytometry on digested singlecell suspensions to evaluate the expansion of lymphatic endothelial cell (LEC) within the EPCAM2CD452 compartment (Fig. 1A) revealed a bimodal pattern of expansion of the gp38+CD31+ LECs
Summary
Using a viralinduced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Inducible model of TLS formation [26], we have dissected the expansion of the lymphatic vascular network within ectopic lymphoid organs that form in the salivary glands.
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