Background/Purpose: T cell entry into and exit from lymph nodes (LNs) exposes T cells to antigens/cytokines required for their activation and regulates the nature of the T cell immune response. However, T cell trafficking through lymphoid tissues in SLE has not been explored. Impaired T cell exit means prolonged exposure to antigen-presenting cells which may lead to increased production of autoantibodies and contribute to disease pathogenesis. Lymphopenia and lymphadenopathy in SLE suggests that there is a disruption in lymphocyte trafficking where lymphocytes are being kept out of circulation and potentially being held in LNs. Egress of T cells from LNs is carefully regulated by the LN microenvironment. A low sphingosine-1-phosphate (S1P) concentration in the LN maintains S1P receptor 1 (S1PR1) expression on T cells which promotes egress by overriding CCR7/CCL21 retention signals. Here, we hypothesize that the LN microenvironment is altered in SLE and contributes to impaired egress of T cells. In this study, we investigate egress of T cells and then delineate a potential mechanism behind changes to egress in SLE.

Methods: We used an inducible lupus mouse model (B6 IMQ) where mice receive topical applications of imiquimod, a TLR7 agonist that produces a high Type 1 interferon signature also present in SLE. To determine if the LN microenvironment affects egress, CFSE labeled naive T cells were intravenously (i.v) injected into the B6 IMQ mice. Egress was assessed by comparing the number of T cells remaining in a LN after blocking their entry with anti-L-selectin to their numbers pre-blockade. S1PR1 expression was used as a readout of S1P levels as S1PR1 is internalized in the presence of high S1P. CD69 can also internalize S1PR1 through physical association and to assess for this, T cells from CD69 knock-out (KO) mice were injected i.v into B6 IMQ. Flow cytometry was performed on skin draining LNs to identify cells and compare expression levels of relevant receptors and cytokines.

Results: Egress of CFSE labeled T cells was significantly impaired in B6 IMQ mice relative to healthy controls. T cell S1PR1 expression was downregulated, suggesting that there is a high S1P level in the LN. Egress of CD69 KO T cells was also impaired and their S1PR1 expression was downregulated, further supporting that high S1P levels lead to the S1PR1 downregulation. CCL21+ fibroblast reticular cells (FRCs) significantly increased in B6 IMQ LNs, suggesting they are also acting as retention signals.

Conclusion: Here our results suggest two changes in the LN microenvironment, an increase in S1P levels and expansion of CCl21+ FRCs, that can promote increased retention of T cells. Current directions are focused on understanding what regulates these changes and what their impact on T cell phenotype is. As impaired egress of T cells can potentially contribute to disease pathogenesis, understanding what regulates T cell exit may potentially open a new area of therapeutic advancement in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-lymph-node-microenvironment-in-sle-mice-is-altered-and-impairs-egress-of-t-lymphocytes/