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Second Signal (second + signal)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Independent CD28 signaling via VAV and SLP-76: a model for in trans costimulation

IMMUNOLOGICAL REVIEWS, Issue 1 2003
Christopher E. Rudd
Summary:, The two-signal theory of T-cell activation dictates that optimal T-cell responses are determined by a least two signals, the primary signal provided by the antigen-receptor complex (TCR/CD3) and the second signal provided by a costimulatory receptor. Recent studies have underlined the importance of in trans costimulation via CD28 in the regulation of transplant rejection. Previous studies have emphasized the ability of CD28 to operate in cis in the amplification of signaling through the T-cell receptor (TCR). Our recent work has demonstrated that CD28 can activate the lipid kinase phosphatidylinositol 3-kinase (PI-3K) and can cooperate with adapters Vav and SLP-76 to influence the induction of interleukin (IL)-2 and IL-4 transcription in the absence of TCR ligation. CD28,PI-3K binding and CD28,VAV/SLP-76 cooperativity provide a pathway to account for in trans costimulation in T-cell immunity. [source]

Sphingosine kinase inhibitor suppresses dendritic cell migration by regulating chemokine receptor expression and impairing p38 mitogen-activated protein kinase

IMMUNOLOGY, Issue 4 2007
In Duk Jung
Summary The migration of dendritic cells (DCs) to secondary lymphoid organs plays a crucial role in the initiation of adaptive immune responses. Although lipopolysaccharide enhances chemokine receptor 7 (CCR7) expression on DCs, the second signal for the migration of DCs toward the chemokine CCL19 remains unknown. In this study, we show that sphingosine kinase inhibitor (SKI) inhibits the migration of DCs toward CCL19 through the down-regulation of CCR7. Inhibition of p38 mitogen-activated protein kinase (MAPK) activation by SKI may be responsible for the SKI-mediated effects on the regulation of chemokine receptor expression. Impairment of DC migration by the inhibition of p38 MAPK and down-regulation of CCR7 expression may contribute to the protective effects of SKI in DC-related disorders. These results suggest that sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering DC migration. [source]

Transmembrane BAFF from rheumatoid synoviocytes requires interleukin-6 to induce the expression of recombination-activating gene in B lymphocytes

ARTHRITIS & RHEUMATISM, Issue 5 2009
Caroline Rochas
Objective B cells that accumulate in the synovial tissue of rheumatoid arthritis (RA) patients revise their receptors due to coordinate expression of recombination-activating gene 1 (RAG-1) and RAG-2 genes. The aim of this study was to determine the mechanisms that control this re-expression. Methods B cells from healthy control subjects were cocultured with fibroblast-like synoviocytes (FLS) from patients with RA and osteoarthritis (OA). Re-expression of RAG messenger RNA (mRNA) and proteins was analyzed by reverse transcription,polymerase chain reaction (RT-PCR) and indirect immunofluorescence. Activity of RAG enzymes was evaluated by flow cytometry to measure variations in immunoglobulin , and , light chain expression and by ligation-mediated,PCR to assess specific DNA breaks. Blocking antibodies, short hairpin RNA, and recombinant cytokine were used to identify the molecules involved in RAG re-expression. Results RA FLS, but not OA FLS, induced B cells to re-express RAG mRNA and proteins. Enzymes were functional, since the ,-to-, ratios decreased and specific DNA breaks were detectable after coculture with RA FLS. Transmembrane BAFF provided the first signal of RAG re-expression, since its down-regulation in RA FLS prevented RAG gene transcription in B cells. The failure of transmembrane BAFF from OA FLS to induce RAG suggests that a second signal was provided by RA FLS. Interleukin-6 (IL-6) is a candidate, since blockade of its receptors precluded transcription of RAG genes by RA FLS. Unless supplemented with IL-6, OA FLS were unable to induce RAG gene expression in normal B cells. Conclusion Two independent signals are required for the induction of RAG gene expression in B cells that infiltrate the synovium of patients with RA. [source]

The Cepheid impostor HD 18391 and its anonymous parent cluster

ASTRONOMISCHE NACHRICHTEN, Issue 8 2009
D.G. Turner
Abstract New and existing photometry for the G0 Ia supergiant HD 18391 is analyzed in order to confirm the nature of the variability previously detected in the star, which lies off the hot edge of the Cepheid instability strip. Small-amplitude variability at a level of ,V = 0.016 ± 0.002 is indicated, with a period of P = 123d.04 ± 0d.06. A weaker second signal may be present at P = 177d.84 ± 0d.18 with ,V = 0.007 ± 0.002, likely corresponding to fundamental mode pulsation if the primary signal represents overtone pulsation (123.04/177.84 = 0.69). The star, with a spectroscopic reddening of EB,V = 1.02 ± 0.003, is associated with heavily-reddened B-type stars in its immediate vicinity that appear to be outlying members of an anonymous young cluster centered ,10, to the west and 1661 ± 73 pc distant. The cluster has nuclear and coronal radii of rn = 3.5, and Rc = 14,, respectively, while the parameters for HD 18391 derived from membership in the cluster with its outlying B stars are consistent with those implied by its Cepheid-like pulsation, provided that it follows the semi-period-luminosity relation expected of such objects. Its inferred luminosity as a cluster member is MV = ,7.76 ± 0.10, its age (9 ± 1) × 106 years, and its evolutionary mass ,19 M,. HD 18391 is not a classical Cepheid, yet it follows the Cepheid period-luminosity relation closely, much like another Cepheid impostor, V810 Cen (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

Molecular modifiers of T cell antigen receptor triggering threshold: the mechanism of CD28 costimulatory receptor

IMMUNOLOGICAL REVIEWS, Issue 1 2003
Oreste Acuto
Summary:, CD28 was thought to represent a prototypic membrane receptor responsible for delivering the classically defined ,second signal' needed to avoid T cell paralysis when recognizing antigen presented by appropriate antigen presenting cells (APCs). Almost two decades after its molecular identification, the mechanism by which this ,second receptor' facilitates clonal expansion and differentiation upon antigen encounter is still not fully elucidated. There may be at least two reasons for this partially gray picture: the use of nonphysiological experimental conditions to study it and the fact that the action of CD28 may be partly masked by the presence of additional T cell surface receptors that also provide some costimulatory signals, although not equivalent to the one delivered through CD28. Thus, instead of aging, the study of CD28 is still a topical subject. What is appearing through work of recent years is that far from being purely qualitative, the CD28 signal provides a key quantitative contribution to potently boost the T cell antigen receptor (TCR) signal. In other words, CD28 is in part a signaling ,sosia' of the TCR. Also, it is clear now that CD28 operates via multiple molecular effects. Still, what we do not understand is the ,qualitative' part of this signal, perhaps due to lack of identification of unique signaling components and/or pathways activated by CD28 only. Here we review a series of recent findings pointing towards novel avenues to better understand the molecular basis of CD28 function. [source]