Clever-1 contributes to lymphocyte entry into the spleen via the red pulp

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Science Immunology  29 Mar 2019:
Vol. 4, Issue 33, eaat0297
DOI: 10.1126/sciimmunol.aat0297

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Splenic portal for lymphocyte entry

Lymphocytes traveling through the body alternate between periods of residence in lymphoid organs and periods of circulation in blood and lymphatic vessels. Tadayon et al. used adoptive transfer of labeled lymphocytes to investigate where circulating lymphocytes first exit the vasculature of the mouse spleen to gain access to the lymphocyte-rich splenic white pulp. A majority of lymphocytes were found in the red pulp zone of the spleen 10 min after transfer. The Clever-1 adhesion and scavenger receptor on endothelial cells was identified as an important facilitator of initial entry of B cells and CD8+ T cells into the red pulp. These findings point to the existence of distinct molecular mechanisms governing how lymphocytes traffic into the spleen compared with the lymph nodes.


Lymphocytes recirculate continuously between the blood and lymphoid organs, a process that is of fundamental importance for proper functioning of the immune system. The molecular mechanisms underlying lymphocyte trafficking to the spleen remain an enigma. Here, we show that lymphocytes enter the spleen preferentially from vessels in the red pulp rather than the marginal sinus or the vasculature in the white pulp. Ex vivo adhesion assays in mice and humans, together with genetic ablation of Clever-1 in mice, indicate that CD8+ T cell and B220+ B cell homing to the spleen via the red pulp is Clever-1 dependent. Moreover, absence of Clever-1 leads to down-regulation of the B cell attractant chemokine, CXCL13, on spleen endothelium. CXCL13 is known to guide B cell trafficking to lymphoid organs, and its lack may contribute to the observed decrease in B cell trafficking into the spleen as well. In summary, this study identifies Clever-1 as an important molecule controlling lymphocyte entry into the spleen, along with a critical role for the splenic red pulp in this regulated trafficking. Furthermore, the results demonstrate that location-specific homing-associated molecules guide lymphocyte entry into the spleen.

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