Defect In Emigration Research Articles

NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells

NLRs (nucleotide-binding domain leucine-rich repeat containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress1,2. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear 2,3. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand binding leucine rich repeat domain, and has been postulated to be a negative regulator of other NLR members including NLRP34–6. We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10−/− mice had a profound defect in helper T cell-driven immune responses to a diverse array of adjuvants including lipopolysaccharide (LPS), aluminium hydroxide (alum) and complete Freund’s adjuvant (CFA). Adaptive immunity was impaired in the absence of NLRP10 due to a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues while upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and independent ligands remained intact. The loss of antigen transport to the draining LN by this migratory DC subset resulted in an almost absolute loss in naïve CD4+ T cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.

Phosphatidylinositol 3-Kinase Regulates Thymic Exit

To understand the role of PI3K during T cell development, we generated transgenic mice expressing the N terminus of the PI3K catalytic subunit (p110(ABD); ABD, adaptor binding domain) in thymocytes. Expression of p110(ABD) activates endogenous p110 and results in the accumulation of mature single-positive CD3(high)heat-stable Ag(low) thymocytes. This is mostly due to a defect in emigration of those cells, as shown by the delayed appearance of peripheral T cells in neonatal transgenic mice and by competitive adoptive transfer experiments. Although the mechanisms underlying these effects of PI3K are not yet clear, our results show an important role for PI3K activity in the regulation of mature thymocyte exit to the periphery.

CD11/CD18-dependent and -independent neutrophil emigration in the lungs: how do neutrophils know which route to take?

Neutrophil adhesion to pulmonary microvascular endothelial cells and migration into the distal air spaces of the lungs occur through at least two adhesion pathways: one that requires the leukocyte adhesion complex, CD11/CD18, and one that does not (1–10). Which pathway is selected appears to depend on the stimulus. The role of CD11/CD18 has been primarily established through the use of antibodies to block the function of this molecule. Neutrophil emigration in response to Escherichia coli , E. coli lipopolysaccharide (LPS), Pseudomonas aeruginosa , immunoglobulin (Ig)G immune complexes, interleukin (IL)-1, and phorbol myristate acetate occurs through adhesion pathways that require CD11/CD18 (1–7). In contrast, Streptococcus pneumoniae , Group B Streptococcus, Staphylococcus aureus , hyperoxia, C5a, and hydrochloric acid elicit neutrophil emigration through pathways not inhibited, despite blockade of the CD11/CD18 adhesion complex (1–10). Even when stimuli elicit emigration primarily through CD18-dependent pathways, anti-CD18 antibodies block neutrophil emigration by only 60 to 80%, leaving about 20 to 40% of neutrophils emigrating through CD18-independent pathways. An autopsy report of a child with complete deficiency of CD11/CD18 (leukocyte adhesion deficiency, type I) showed neutrophils and monocytes within the alveoli and small airways (11), suggesting that human neutrophils, as well as those of mice and rats, can use CD11/ CD18-independent mechanisms of neutrophil emigration. It seems important to note that this adhesion and migration most likely occurs after neutrophils are already sequestered within the pulmonary capillaries at sites of infection or injury. In contrast to the postcapillary venules of the systemic circulation, where neutrophil emigration commonly occurs, the pulmonary capillaries are the site of emigration in the pulmonary circulation, and rolling (selectin-mediated or other) does not occur (12). The initial sequestration of neutrophils appears to involve other mechanisms, and recognized adhesion molecules do not appear to play a role. The mechanisms underlying this sequestration have been discussed elsewhere (13–15) and will not be mentioned further here. Initially, the CD11/CD18-independent adhesion pathway was thought to occur only in the lungs, perhaps because of the unique structure of the pulmonary capillary bed and the unique cell types present in the lungs, including alveolar macrophages. In the skin, anti-CD18 antibodies blocked neutrophil emigration in response to numerous stimuli, and the inhibition was complete (1, 16). However, Jaeschke and colleagues and Kubes and associates found that sequestration of neutrophils within the sinusoids of the liver during endotoxemia does not require either CD11/CD18 or the selectins (17–19). The hepatic sinusoids are thus another site where alternative pathways are important, and other sites may yet be identified. Because monoclonal antibodies block only one site on the CD11/CD18 heterodimer, there was always the concern that another site on this complex was mediating this so-called CD11/CD18-independent neutrophil emigration. Dr. Arthur L. Beaudet generated mice with a complete deficiency of the CD18 molecule (20, 21). However, similar to the patients, these mice have extraordinarily high neutrophil counts measuring 5 to 40 or more times higher than wild-type mice, even as neonates (20, 21). Neutrophil emigration into either E. coli LPS or S. pneumoniae pneumonia was actually increased compared with wild-type mice. However, the increase was not as great as the increase in circulating count, making these data extremely difficult to interpret because the relationship between circulating and emigrating neutrophils is complex and not linear (21). In an attempt to circumvent this problem, wild-type mice were lethally irradiated, and their bone marrows were reconstituted with a mixture of CD18 nulland wild-type stem cells obtained from 14-d fetuses. These studies showed that in response to E. coli LPS, the CD18 null neutrophils showed a defect in their emigration into the air spaces compared with wild-type neutrophils in the same mouse, whereas CD18 null neutrophils showed no defect in emigration induced by S. pneumoniae (22). These studies indicate that the CD11/CD18-independent emigration observed using blocking antibodies was truly independent and did not require any part of the CD11/CD18 leukocyte complex. The studies presented in the paper by Mackarel and colleagues in this issue of the American Journal of Respiratory Cell and Molecular Biology are, to our knowledge, the ( Received in original form July 14, 2000 )

Combinatorial requirements for adhesion molecules in mediating neutrophil emigration during bacterial peritonitis in mice.

To investigate the requirements for adhesion molecules in neutrophil emigration during peritonitis, mice received intraperitoneal injections of Streptococcus pneumoniae while the functions of multiple adhesion molecules were blocked. Emigration after 4 h was compromised by antibodies against ICAM-1 or genetic deficiency of ICAM-1. Anti-CD11a/CD18 antibodies decreased emigration in ICAM-1 mutant mice, suggesting that ICAM-1 independent emigration requires CD11/CD18 complexes. In contrast, mice mutant in ICAM-1 plus E-selectin showed no defect in emigration, suggesting that E-selectin commits neutrophils to an ICAM-1-dependent pathway during streptococcal peritonitis. However, in mutant mice lacking the three endothelial adhesion molecules E-selectin, P-selectin, and ICAM-1, emigration after 4 h was significantly compromised. Thus, P-selectin is essential to ICAM-1- and E-selectin-independent acute peritoneal inflammation. After 24 h of peritonitis, there were no differences between WT and E-selectin/P-selectin/ICAM-1 mutant mice, demonstrating that these endothelial adhesion molecules are not essential to neutrophil emigration during later stages of peritonitis.