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Summary Tetraspanins regulate key processes in immune cells; however, the function of the leukocyte-restricted tetraspanin CD53 is unknown. Here we show that CD53 is essential for lymphocyte recirculation. Lymph nodes of Cd53−/− mice were smaller than those of wild-type mice due to a marked reduction in B cells and a 50% decrease in T cells. This reduced cellularity reflected an inability of Cd53−/− B and T cells to efficiently home to lymph nodes, due to the near absence of L-selectin from Cd53−/− B cells and reduced stability of L-selectin on Cd53−/− T cells. Further analyses, including on human lymphocytes, showed that CD53 stabilizes L-selectin surface expression and may restrain L-selectin shedding via both ADAM17-dependent and ADAM17-independent mechanisms. The disruption in lymphocyte recirculation in Cd53−/− mice led to impaired immune responses dependent on antigen delivery to lymph nodes. Together these findings demonstrate an essential role for CD53 in lymphocyte trafficking and immunity., Graphical Abstract, Highlights • CD53 is essential for lymph node cellularity as Cd53−/− lymph nodes lack T and B cells • CD53 is essential for lymphocyte homing to lymph nodes • CD53 stabilizes L-selectin cell surface expression and may restrain shedding • Impaired lymphocyte homing leads to diminished immune responses in Cd53−/− mice, Molecular Mechanism of Behavior; Immunology; Immune Response; Specialized Functions of Cells