Expression of CD226 is associated to but not required for NK cell education

AbstractDNAX accessory molecule-1 (DNAM-1, also known as CD226) is an activating receptor expressed on subsets of natural killer (NK) and T cells, interacts with its ligands CD155 or CD112, and has co-varied expression with inhibitory receptors. Since inhibitory receptors control NK-cell activation and are necessary for MHC-I-dependent education, we investigated whether DNAM-1 expression is also involved in NK-cell education. Here we show an MHC-I-dependent correlation between DNAM-1 expression and NK-cell education, and an association between DNAM-1 and NKG2A that occurs even in MHC class I deficient mice. DNAM-1 is expressed early during NK-cell development, precedes the expression of MHC-I-specific inhibitory receptors, and is modulated in an education-dependent fashion. Cd226−/− mice have missing self-responses and NK cells with a normal receptor repertoire. We propose a model in which NK-cell education prevents or delays downregulation of DNAM-1. This molecule endows educated NK cells with enhanced effector functions but is dispensable for education.</jats:p

Cooperating Mechanisms of CXCR5 and CCR7 in Development and Organization of Secondary Lymphoid Organs

Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3− CD4+ interleukin (IL)-7Rαhi cells to sites of future organ development. CD3− CD4+ IL-7Rαhi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5−/− CCR7−/− double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3− CD4+ IL-7Rαhi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5−/− CCR7−/− mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5−/− CCR7−/− mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization

Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets.

Invariant natural killer T (iNKT) cells comprise a subpopulation of innate lymphocytes developing in thymus. A new model proposes subdividing murine iNKT cells into iNKT1, 2 and 17 cells. Here, we use transcriptome analyses of iNKT1, 2 and 17 subsets isolated from BALB/c and C57BL/6 thymi to identify candidate genes that may affect iNKT cell development, migration or function. We show that Fcɛr1γ is involved in generation of iNKT1 cells and that SerpinB1 modulates frequency of iNKT17 cells. Moreover, a considerable proportion of iNKT17 cells express IL-4 and IL-17 simultaneously. The results presented not only validate the usefulness of the iNKT1/2/17-concept but also provide new insights into iNKT cell biology

Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire

SummaryThymic selection requires signaling by the protein tyrosine kinase Lck to generate T cells expressing αβ T cell antigen receptors (TCR). For reasons not understood, the thymus selects only αβTCR that are restricted by major histocompatibility complex (MHC)-encoded determinants. Here, we report that Lck proteins that were coreceptor associated promoted thymic selection of conventionally MHC-restricted TCR, but Lck proteins that were coreceptor free promoted thymic selection of MHC-independent TCR. Transgenic TCR with MHC-independent specificity for CD155 utilized coreceptor-free Lck to signal thymic selection in the absence of MHC, unlike any transgenic TCR previously described. Thus, the thymus can select either MHC-restricted or MHC-independent αβTCR depending on whether Lck is coreceptor associated or coreceptor free. We conclude that the intracellular state of Lck determines the specificity of thymic selection and that Lck association with coreceptor proteins during thymic selection is the mechanism by which MHC restriction is imposed on a randomly generated αβTCR repertoire

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Coming of Age: CD96 Emerges as Modulator of Immune Responses

CD96 represents a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD96 is expressed mainly by cells of hematopoietic origin, in particular on T and NK cells. Upon interaction with CD155 present on target cells, CD96 was found to inhibit mouse NK cells, and absence of this interaction either by blocking with antibody or knockout of CD96 showed profound beneficial effects in containment of tumors and metastatic spread in murine model systems. However, our knowledge regarding CD96 functions remains fragmentary. In this review, we will discuss structural features of CD96 and their putative impact on function as well as some unresolved issues such as a potential activation that may be conferred by human but not mouse CD96. This is of importance for translation into human cancer therapy. We will also address CD96 activities in the context of the immune regulatory network that consists of CD155, CD96, CD226, and TIGIT

The Poliovirus Receptor CD155 Mediates Cell-to-Matrix Contacts by Specifically Binding to Vitronectin

AbstractThe human receptor for poliovirus (CD155) is an immunoglobulin-like molecule with unknown normal function(s). Here we provide evidence that CD155 binds specifically to vitronectin with a dissociation constant (Kd) of 72 nM as determined by surface plasmon resonance. Based on sequence homology to the CD155 gene, three poliovirus receptor-related genes (PRR1, PRR2, and PRR3) were cloned recently. PRR proteins were reported by others to mediate homophilic cell adhesion. Neither PRR1 nor PRR2 binds poliovirus and it is assumed that their physiological functions differ from that of CD155. Indeed, mPRR2 was found to bind to vitronectin only weakly, while its self-adhesion activity is characterized by a Kd of 310 nM. Moreover, there is no evidence for CD155 self-adhesion. Both CD155 and vitronectin colocalize to follicular dendritic cells and B cells inside the germinal centers of secondary lymphoid tissue (tonsils)—an observation suggesting that the CD155/vitronectin interaction is required for the establishment of a proper immune response in this particular context