L-Selectin

L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLex) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.

L-selectin is a type I transmembrane cell adhesion molecule expressed on most circulating leukocytes, including neutrophils. Engagement of L-selectin with endothelial-derived ligands initiates neutrophil tethering and rolling behaviour along luminal walls of post-capillary venules, constituting the first step of the multi-step adhesion cascade. There is a large body of evidence to suggest that signalling downstream of L-selectin can influence neutrophil behaviour: adhesion, migration and priming. This review will cover aspects of L-selectin form and function and introduce the "triad of L-selectin regulation", highlighting the inextricable links between adhesion, signalling and ectodomain shedding and also highlighting the cytosolic proteins that interconnect them. Recent advances in how L-selectin impacts priming, transendothelial migration (TEM) and cell polarity will also be discussed.

Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.

IntroductionRecent findings reveal that the precursors of exhausted CD8+ T (CD8+ Tpex) cells possess stem-like signatures in tumor immunity, which originate from tumor draining lymph node (TdLN)-derived tumor-specific memory (CD8+ TTSM) cells. Both of these T subsets can be collectively referred to as stem-like CD8+ T cells, which demonstrate robust self-renewal ability and can proliferate and differentiate into transitory effector-like exhausted T cells (Texint). There are reports that chemotherapeutic drugs can promote the antitumor immune responses of patients by increasing the number of CD8+ T cells; however, whether chemotherapeutic drugs increase these two stem-like CD8+ T cells remain further exploration.MethodsTpex cell-associated subpopulations in human colorectal tumors were analyzed by using single-cell sequencing data. CT26 and B16 tumor models of wild type and Eomes conditional knockout mice were constructed, and the changes of TTSM, Tpex and Tex subsets in mice were dissected by flow cytometry after treatment with decitabine (DAC), doxorubicin (DOX) and 5-Fluorouracil (5-FU).ResultsIn this study, we demonstrated that DAC and 5-FU expanded CD8+ TTSM cells in TdLNs. At the same time, we validated that DAC and 5-FU substantially promoted the expansion of CD62L+CD8+ Tpex cells and subsequently increased effector function of CX3CR1+ CD8+ Texint cells. In addition, the conditional knockout of transcription factor Eomes in CD8+ T cells partially eliminated DAC-amplified CD62L+ CD8+ Tpex cells, but had no effect on such CD8+ T subset expanded by 5-FU.ConclusionThe present study demonstrated that both DAC and 5-FU promoted the differentiation of stem-like CD8+ TTSM cells in TdLNs and significantly enhanced the differentiation and expansion of stem-like CD62L+ CD8+ Tpex and CX3CR1+ Texint cells in tumor microenvironment. The knockout of Eomes partially influenced the role of DAC in promoting the differentiation and expansion of stem-like CD8+ T cells.