Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies revealed a linkage between increased K+ current and lymphocyte activation upon non-specific stimulation with mitogenic lectins and antibodies. So far no information is available about the behaviour of K+ currents in specifically autoantigen-stimulated lymphocytes. Therefore, we have investigated K+ currents in encephalitogenic T line cells, specifically stimulated with myelin basic protein, using the whole-cell patch-clamp technique. In parallel, the T cell activation marker interleukin-2 (IL-2) receptor was measured quantitatively by flow cytometry. Outward currents were observed in response to depolarizing voltage steps from a holding potential of -80mV. The peak current density increased with more positive membrane potentials, where the current threshold was about -40mV and the maximum conductance was 1.22nS/pF. This current was characterized by a fast activation and a fast inactivation with half maximal inactivation at -67mV. The sensitivity of the peak current to K+ channel blocking agents was as follows: 4-aminopyridine (4-AP) had a half blocking concentration of 0.4mM and a maximal block of 83.7% at 10mM 4-AP, tetraethyl-ammonium caused a block of 6% at 0.1mM, 15% at 1mM and 40% at 10mM, charybdotoxin blocked 90% at 100nM, whereas iberiotoxin had no effect (all values at a clamped membrane potential of +30mV). The encephalitogenic T cells used in our study reach their highest encephalitogenic potency on day 3 to 4 after the onset of restimulation. Furthermore, K+ currents were measured during the whole course of an in vitro restimulation cycle. The peak currents normalized to cell capacitance reached their maximum on day 2 (326+/- 52.8pA/pF, n = 4) and decreased thereafter as follows: day 3: 139.7 +/- 7.87pA/pF (n = 27), day 4: 85.4 +/- 8.95pA/pF (n = 28) and day 5: 40.9 +/- 7.45pA/pF (n = 17). The activation and inactivation characteristics of the current and its responses to selective blockers were similar at all days after restimulation. In contrast to the K+ current, IL-2 receptor expression was maintained on > 95% of cells until day 6 after restimulation. In conclusion, the K+ currents measured in rat encephalitogenic T cells resemble n-type voltage-gated K+ currents described in mice and man. The comparison of K+ current, IL-2 receptor expression and encephalitogenic potency let us suppose that the observed K+ current represents an early event of specific T cell activation and can serve as a parameter of high functional activity of T cells corresponding to their encephalitogenicity.
 ...
PMID:K+ currents of encephalitogenic memory T cells decrease with encephalitogenicity while interleukin-2 (IL-2) receptor expression remains stable during IL-2 dependent cell expansion. 966 24

Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram on several T helper 1-(TNF-alpha, TNF-beta, IFN-gamma) and T helper 2-like cytokines (IL-4, IL-13) as well as IL-10 revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10. This profile suggest that rolipram differs from other currently used immunomodulatory drugs.
 ...
PMID:Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones. 1043 48

In this study, we assessed the expression of activation markers on gammadelta T cells in central nervous system (CNS) lesions of SJL mice adoptively sensitized to develop experimental autoimmune encephalomyelitis (EAE) using myelin basic protein-reactive T cells. Although disease expression is known to be dependent upon T cells that express the alphabeta T cell receptor (TCR), a role for gammadelta T cells has been implicated in some studies but not in others. Using three-color flow cytometric analysis of both total and gammadelta T cells in spleen and CNS, the data showed that expression of CD69 (early activation marker), CD62L (lymphocyte homing receptor), CD25 (IL-2Ralpha), CD122 (IL-2Rbeta) and CD95/CD95L (Fas/FasL), fluctuated on gammadelta T cells in EAE lesions in a disease-related fashion. Furthermore, the pattern of expression for these markers on gammadelta T cells was distinct from that found on the total lymphocyte population. Cytokine analysis of gammadelta T cells in the CNS demonstrated a bias towards a Th1-like cytokine profile. From these data, we conclude that gammadelta T cells in EAE lesions display an activated phenotype and form a dynamic component of the total lymphocyte population in the CNS, supporting a contributory role for these cells.
 ...
PMID:gammadelta T cells express activation markers in the central nervous system of mice with chronic-relapsing experimental autoimmune encephalomyelitis. 1177 50

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology. EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains. In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin (PT). T cell responses were induced to myelin basic protein. Autoreactive T cells could be totally blocked by the in vitro treatment with CTLA4Ig, a protein that blocks the costimulation of autoreactive T cells. The addition of IL-2 could reverse the inhibition seen in vitro with CTLA4Ig. The effects of inhibition of B7 costimulation were also examined by an analysis of cytokine responses and IL-2 receptor on T cells. CTLA4Ig treatment in vitro reduced the expression of IL-2 receptor on T cells, enhanced T cell apoptosis and decreased the synthesis of IL-2, IFN-gamma and TNF-alpha. CTLA4Ig treatment had no effect on IL-10 synthesis by T cells, a cytokine implicated in the functions of regulatory T cell subsets. Overall, our studies support the rationale of B7 blocking therapies as a potential treatment for models of multiple sclerosis. The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity.
 ...
PMID:Experimental autoimmune encephalomyelitis in the Wistar rat: dependence of MBP-specific T cell responsiveness on B7 costimulation. 1238 44

CD4(+)CD25(high) T regulatory (Tr) cells, representing high IL-2 receptor alpha chain expressing cells, have been shown to inhibit proliferation and cytokine secretion by CD4(+) T cells that are assumed to represent important effector cells in auto-aggressive immunity. Tr cells may therefore be considered of importance in the pathogenesis of multiple sclerosis (MS). Glatiramer acetate (GA; Copaxone) is approved as a disease-modulating agent that ameliorates the course of MS. The goal of this study was to examine in vitro effects of GA on Tr cells from MS patients subgrouped according to treatment without or with disease-modulating drugs, and healthy controls (HC). Three-colour flow cytometry was used to investigate in vitro influence of GA, and of the encephalitogenic myelin basic protein (MBP) peptide 83-89 as control, on the blood Tr cell proportion and on their functionally important cell surface molecules CD45RO, CD69, CD95 and HLA-DR, and on intracellular CTLA-4 and IL-10. Irrespective of exposure to GA or MBP((83-99)), levels of blood Tr cells expressing HLA-DR remained low in untreated MS patients and HC compared to the three treated MS patient groups. In vitro exposure to GA resulted in elevated levels of IL-10 producing Tr cells in all MS patient groups irrespective of receiving treatment as well as in HC. Exposure to GA or MBP((83-99)) had no effects on levels of Tr cells expressing other above-mentioned molecules. We conclude that GA induces elevated IL-10 production by Tr cells that is uniform and independent of ongoing MS treatment with IFN-beta or GA or IFN-beta+GA.
 ...
PMID:Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis. 1459 6

Expression of the IL-2 receptor alpha chain (CD25) by peripheral CD4 T cells follows cellular activation. However, CD25 expression by CD4 cells is widely used as a marker to identify regulatory T cells (T(R)), although cells with regulatory properties are also found in the CD4+CD25- subset. By using in vivo functional assays and Foxp3 expression as a faithful marker of T(R) differentiation, we have evaluated the requirements for CD25 expression by peripheral T(R). We first show that in vivo depletion of CD25+ cells prevents the development of spontaneous encephalomyelitis in recombination-activating gene (RAG)-deficient anti-myelin basic protein T cell antigen receptor (TCR) transgenic mice, and allows disease induction in otherwise healthy RAG-competent transgenic mice. Similar treatment in normal thymectomized animals is followed by the fast recovery of a normal number of CD25+ T(R). Consistently, Foxp3-expressing T(R) encompassed in the CD25- cell population convert to CD25+ after homeostatic expansion and are selectable by IL-2 in vitro. Surface expression of CD25 on T(R) is controlled by the activity of conventional CD4 cells and is fully labile because it can be lost and regained without affecting the functional potential of the cells. These findings reveal that Foxp3-expressing CD25- cells constitute a peripheral reservoir of differentiated T(R), recruited to the CD25+ pool upon homeostatic expansion and/or activation. This analysis, together with the notion that physiological commitment of T(R) takes place exclusively in the thymus should help for the interpretation of experiments assessing peripheral T(R) differentiation from naive CD4 T cells, defined as CD25-.
 ...
PMID:Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. 1575 6

Immunization with irradiated autologous T cells (T cell vaccination) is shown to induce regulatory T cell responses that are poorly understood. In this study, CD4(+) regulatory T cell lines were generated from patients with multiple sclerosis that received immunization with irradiated autologous myelin basic protein-reactive T cells. The resulting CD4(+) regulatory T cell lines had marked inhibition on autologous myelin basic protein-reactive T cells and displayed two distinctive patterns distinguishable by the expression of transcription factor Foxp3 and cytokine profile. The majority of the T cell lines had high Foxp3 expression and secreted both IFN-gamma and IL-10 as compared with the other pattern characteristic of low Foxp3 expression and predominant production of IL-10 but not IFN-gamma. CD4(+) regulatory T cell lines of both patterns expressed CD25 and reacted with activated autologous T cells but not resting T cells, irrespective of antigen specificity of the target T cells. It was evident that they recognized preferentially a synthetic peptide corresponding to residues 61-73 of the IL-2 receptor alpha chain. T cell vaccination correlated with increased Foxp3 expression and T cell reactivity to peptide 61-73. The findings have important implications in the understanding of the role of CD4(+) regulatory T cell response induced by T cell vaccination.
 ...
PMID:CD4+ regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis. 1654 38


<< Previous 1 2