Adjuvant activity of the Toll receptor 9 agonist CpG 1826 was compared when given subcutaneously (s.c.) together with ovalbumin (s.
View Article and Find Full Text PDFSkin tissue resident memory T cells (T) provide superior protection to a second infection. In this study, we evaluated the use of topical CpG oligodeoxynucleotide (ODN) as adjuvant to generate skin T in mice. Topical or s.
View Article and Find Full Text PDFP-selectin expressed on activated endothelia and platelets supports recruitment of leukocytes expressing P-selectin ligand to sites of inflammation. While monitoring P-selectin ligand expression on activated CD8+ T cells in murine adoptive transfer models, we observed two distinct ligands on responding donor cells, the canonical cell-intrinsic P-selectin ligand PSGL-1 and a second undocumented P-selectin ligand we provisionally named PSL2. PSL2 is unusual among selectin ligands in that it is cell-extrinsic, loaded onto L-selectin expressed by activated T cells but not L-selectin on resting naïve CD8+ T cells.
View Article and Find Full Text PDFInterleukin-7 (IL-7) is essential for the development of T cells in humans and mice where deficiencies in IL-7 signaling result in severe immunodeficiency. T cells require IL-7 at multiple points during development; however, it is unclear when IL-7 is first necessary. We observed that mice with impaired IL-7 signaling had a large reduction in the number of early thymic progenitors (ETPs) while mice that overexpress IL-7 had greatly increased numbers of ETPs.
View Article and Find Full Text PDFP-selectin glycoprotein ligand-1 (PSGL-1), a heavily glycosylated sialomucin expressed on most leukocytes, has dual function as a selectin ligand for leukocyte rolling on vascular selectins expressed in inflammation and as a facilitator of resting T cell homing into lymphoid organs. In this article, we document disturbances in T cell homeostasis present in PSGL-1(null) mice. Naive CD4(+) and CD8(+) T cell frequencies were profoundly reduced in blood, whereas T cell numbers in lymph nodes and spleen were at or near normal levels.
View Article and Find Full Text PDFThe substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues.
View Article and Find Full Text PDFThe omentum is of interest in the context of obesity-related metabolic disease where adipose tissue exhibits inflammatory changes; however, the immunology of the omentum is underexplored. The greater omentum is draped from the stomach and consists predominantly of adipose tissue studded with lymphoreticular aggregations (milky spots) that distinguish it from other visceral adipose tissues. Milky spots are thought to contain and conduct leukocytes in transit from the blood to the peritoneal cavity, particularly during peritonitis.
View Article and Find Full Text PDFP-selectin glycoprotein ligand 1 (PSGL-1) is central to the trafficking of immune effector cells to areas of inflammation through direct interactions with P-selectin, E-selectin and L-selectin. Here we show that PSGL-1 was also required for efficient homing of resting T cells to secondary lymphoid organs but functioned independently of selectin binding. PSGL-1 mediated an enhanced chemotactic T cell response to the secondary lymphoid organ chemokines CCL21 and CCL19 but not to CXCL12 or to inflammatory chemokines.
View Article and Find Full Text PDFUsing noncompetitive methodologies comparing CD43(+/+) and CD43(-/-) mice, it has been reported that CD43(-/-) leukocytes exhibit reduced recruitment efficiency to sites of inflammation. More recent analyses demonstrate that CD43 on activated T cells can function as an E-selectin ligand (E-SelL) in vitro, suggesting that CD43 might promote rolling interactions during recruitment of leukocytes and account for the reported recruitment deficits in CD43(-/-) T cells and neutrophils in vivo. Internally controlled competitive in vivo methods using fluorescent tracking dyes were applied to compare recruitment efficiency of CD43(+/+) vs CD43(-/-) activated T cells to inflamed skin and of peripheral blood neutrophils to inflamed peritoneum.
View Article and Find Full Text PDFThe molecular mechanisms that direct the migration of early T lymphocyte progenitors to the thymus are unknown. We show here that P-selectin is expressed by thymic endothelium and that lymphoid progenitors in bone marrow and thymus bind P-selectin. Parabiosis, competitive thymus reconstitution and short-term homing assays indicated that P-selectin and its ligand PSGL-1 are functionally important components of the thymic homing process.
View Article and Find Full Text PDFIn vitro studies have demonstrated that IL-2 and IL-12 can support formation of P-selectin ligands (P-SelL) in activated T cells, ligands that are variably required for efficient lymphocyte recruitment to sites of inflammation. To ascertain whether these cytokines were required for P-SelL formation in vivo, TCR transgenic CD8 T cells specific for male Ag (HY) were transferred into male mice under conditions in which either IL-2 and/or IL-15 or IL-12Rp40 were absent. P-SelL formation at day 2 was unperturbed in HY-TCR IL-2(null) CD8 T cells responding in doubly deficient IL-2(null)IL-12(null) or IL-2(null)IL-15(null) male recipients.
View Article and Find Full Text PDFObjective: To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood-brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10-12 months of age.
Methods: We assessed BBB integrity using well-established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate.
Results: BBB permeability is increased in the cerebral cortex of 10-month-old Tg2576 mice preceding Alzheimer disease pathology presentation.
Thymic negative selection and contraction of responding T cell oligoclones after infection represent important cell ablation processes required for maintaining T cell homeostasis. It has been proposed that galectin 1 contributes to these processes through interaction with lactosyl sequences principally on cell surface glycoproteins bearing core 2 (C2GnT1)-branched O-glycans. According to this model, specific T cell surface proteins cross-linked by galectin 1 induce signaling, ligand redistribution, and apoptosis in both immature thymocytes and activated T cells.
View Article and Find Full Text PDFIn T lymphocytes, sustained calcium (Ca2+) influx through Ca2+ channels localized in the plasma membrane is critical for T cell activation and proliferation. Previous studies indicated that voltage-dependent Ca2+ channels (VDCCs) play a role in Ca2+ mobilization during T lymphocyte activation. However, the role of VDCCs in otherwise nonexcitable cells is still poorly understood.
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