Studienarbeit
Thema
T cell ion channels and their role for activation
T-Zell Aktivierung und die Rolle von Ionenkanälen
T cell ion channels and their role for T cell activation
1.) T cells
As well as B-cells and natural killer cells (NK), T cells belong to the lymphocytes and present a hallmark of the adaptive immunity in vertebrates. All T cells originate from a progenitor cell in the bone narrow and undergo maturation in the thymus. During maturation the T lymphocytes are being provided with different membrane-bound receptors and cell surface markers distinguishing distinct T cell subsets with unique functions.
T cell subsets: Depending on the composition of their T cell antigen receptor (TCR) the T cells are subdivided into αβ-T cells and γδ-T cells. Αβ-T cells account for the biggest part of the T cells with around 90-95% and represent about 70% of all peripheral blood mononuclear cells (PBMC). They circulate continuously from the bloodstream to the lymphatic system and lymphoid organs back to the blood, making contact with antigen presenting cells (APCs).
The most important factor for the recognition of different antigens is the T cell receptor (TCR). The α- and β-chains of the heterodimeric TCR are composed of a variable and a constant region, which during maturation are spliced together into a single type of functional αβ-TCR which differs in every T cell.
A further determination of αβ-T cells is made by the expression of different co-receptors on the plasma membrane during thymic maturation. T cells express either a CD4 co-receptor (CD4+) or a CD8 co-receptor (CD8+) involved in TCR signaling on their cell surface. CD4+ cells are also known as T-helper cells (Th) and can recognize foreign peptides mainly from extracellular spaces bound to MHC class II molecules, expressed by professional APCs, such as dendritic cells (DCs), macrophages and B cells.
CD8+ cells on the other hand are also known as cytotoxic T cells (Tcyt).
They recognize foreign peptides mainly from the cytosol bound to MHC class I molecules, expressedby all nucleated cells (Germain 2002).
CD8+ cytotoxic T cells mediate the killing of target cells via cytokines like Interferon gamma (IFNγ) or tumor necrosis factor alpha (TNFα) as well as cytotoxic molecules like granzyme B or perforin (Sprent et al. 2002). CD4+ T-helper cells on the other hand are important regulators of the immune response and can be further divided into a broad range of subsets with specialized functions.
Their classification is based upon the production of different cytokines and the expression of characteristic transcription factors. The CD4 + cells can be principally grouped into five different main lineages including T Helper cells (Th) Th1, Th2, Th17, regulatory T cells (Treg) and follicular Helper cells (TFH) (reviewed in Geginat et al. 2013). Th1 cells are characterized by IFNγ- and TFNβ-production and are responsible for activation of cytotoxic T cells or macrophages and protection against in.....[read full text]
This paragraph is not visible in the preview.
Please downloadthe paper. Signaling pathways: Three main pathways lead to T cell activation after TCR triggering. The first step in the signaling cascade of T cell activation is the phosphorylation of the CD3 ITAMs by the co-receptor-associated Lck kinase leading to recruitment of further signaling complexes and results in the activation of phospholipase Cγ1 (PLCγ1), which is the initiator for important downstream pathways (Beach et al. 2007).
In the first pathway PLC then hydrolyzes PIP2 into IP3 and DAG (Rhee 2003). In the next step, IP3 induces calcium ion release from intracellular stores (e.g. the ER). Depletion of Ca2+ also leads to the opening of calcium channels (CRAC channels) in the plasma membrane further increasing the calcium signal. Calcium continues the signal by activating calcineurin via calmodulin.
Calcineurin in turn dephosphorylates the nuclear factor of activated T cells (NFAT) enabling it to enter the nucleus and operate as a transcription factor. For NFAT translocation a prolonged Ca2+-entry is needed (Hogan et al. 2003). The second major pathway includes the activation of protein kinase C θ by DAG which via further messengers activates the transcription factor NF-KB (Wegener et al. 2006). Furthermore, NF-
KB can be activated by strong and short increases of intracellular Ca2+ levels (Schulze-Luehrmann & Ghosh 2006). Thirdly, DAG is also able to activate Ras, which continues the signal through phosphorylation events finally initiating the formation of the master transcription factor activator protein 1 (AP-1) (reviewed in Genot & Cantrell 2000).
The activation of these transcription factors does not only induce transcription of specific effector molecules specific for each cell but also induces IL-2 production promoting T cell growth (Jain 1995).
2.) .....
This paragraph is not visible in the preview.
Please downloadthe paper. Potassium channels: The Kv1.3 channel is activated at membrane potentials depolarized over -60mV, leading to a K+ outward current along the electrochemical gradient hyperpolarizing the membrane potential (Cahalan et al. 1985). Inactivation of Kv1.3 follows sustained depolarization of the membrane potential due to conformational changes (Panyi et al. 1995). Another important potassium channel is KCa3.1 activated by Ca2+ concentrations above 200nM.
Through the C-terminal bound calmodulin at the Kv1.3 subunit the Ca2+ concentrations are sensed and result in rapid channel activation upon Ca2+ binding (Grissmer 1993). Similarly to Kv1.3 channels, activation of KCa3.1 leads to a K+ selective outward current that hyperpolarizes the membrane potential sustaining a permissive potential for prolonged Ca2+ inward current (Varga et al. 2010).
Interestingly, both potassium channels can be specifically blocked by toxins or small organic compounds (Kalman 1998; Srivastava et al. 2008; Srivastava et al. 2005) and show different expression patterns on different T cell subtypes, increasing from resting or naïve to active subtypes (Cahalan et al. 2001). Since blockade of potassium channels, especially Kv1.3, results in suppression of proliferation and effector functions they have been proven as attractive targets for selective immunosuppression in autoimmune disorders.
For example, since T cells are involved in acute rejection of transplanted organs and acute graft-versus-host disease, the blocking of Kv1.3 and KCa3.1 channels could enhance treatment of these clinical implications (Chandy et al. 2004). Thus, ion channels play an important role in T cell activation and functioning. But still, the whole mechanism has not yet been fully understood and a lot of other ion channels have not yet been investigated.
Bibliography:
Artyomov, M.N. et al., 2010. CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. Proceedings of the National Academy of Sciences of the United States of America, 107(39), pp.16916–21.
Beach, D. et al., 2007. Dual role of SLP-76 in mediating T cell receptor-induced activation of phospholipase C-gamma1. The Journal of biological chemistry, 282(5), pp.....
This paragraph is not visible in the preview.
Please downloadthe paper. Geginat, J. et al., 2013. The CD4-centered universe of human T cell subsets. Seminars in Immunology, 25(4), pp.252–262.
Genot, E. & Cantrell, D.A., 2000. Ras regulation and function in lymphocytes. Current Opinion in Immunology, 12(3), pp.289–294.
Germain, R.N., 2002. T-cell development and the CD4-CD8 lineage decision. Nature reviews. Immunology, 2(5), pp.309–22.
Grissmer, S., 1993. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology. The Journal of General Physiology, 102(4), pp.601–630.
Guy, C.S. & Vignali, D.A.A., 2009. Organization of proximal signal initiation at the TCR:CD3 complex. Immunological reviews, 232(1), pp.7–21.
Hogan, P.G. et al., 2003. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & development, 17(18), pp.2205–32.
Hori, S., Nomura, T. & Sakaguchi, S., 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science (New York, N.Y.).....
This paragraph is not visible in the preview.
Please downloadthe paper. Rhee, S.G., 2003. REGULATION OF PHOSPHOINOSITIDE-SPECIFIC PHOSPHOLIPASE C*.
Schulze-Luehrmann, J. & Ghosh, S., 2006. Antigen-Receptor Signaling to Nuclear Factor κB. Immunity, 25(5), pp.701–715.].
Sprent, J., Judge, A.D. & Zhang, X., 2002. Cytokines and memory-phenotype CD8+ cells. Advances in experimental medicine and biology, 512, pp.147–53.
Srivastava, S. et al., 2008. Protein histidine phosphatase 1 negatively regulates CD4 T cells by inhibiting the K+ channel KCa3.1. Proceedings of the National Academy of Sciences of the United States of America, 105(38), pp.14442–6.
Srivastava, S. et al., 2005. The phosphatidylinositol 3-phosphate phosphatase myotubularin- related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1. Molecular and cellular biology, 25(9), pp.3630–8.
Valitutti, S., 1995. Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. Journal of Experimental Medicine, 181(2), pp.577–584.
Varga, Z., Hajdu, P. & Panyi, G., 2010. Ion channels in T lymphocytes: an update on facts, mechanisms and therapeutic targeting in autoimmune diseases. Immunology letters, 130(1–2), .....
This paragraph is not visible in the preview.
Please downloadthe paper. Zweifach, A. & Lewis, R.S., 1995. Slow calcium-dependent inactivation of depletion-activated calcium current. Store-dependent and -independent mechanisms. The Journal of biological chemistry, 270(24), pp......
![stern]() ![stern]() ![stern]() ![stern]() ![stern]() "Redaktion" | 2018-01-08 |
Dies ist die Bewertungsnote welche sich nach der ersten Prüfung des Dokuments aus den Teilnoten Inhalt, Vollständigkeit, Rechtschreibung und Benotung ergibt. Unser Team prüft alle Dokumente vor der Freigabe händisch und vergibt nach diesen Kriterien eine Gesamtnote:
1) Inhalt und Aktualität
2) Rechschreibung und Stil
3) Ergebnisse und Vollständigkeit
4) Aufbereitung und Präsentation
5) Quellen (falls vorhanden/nötig)
Bitte kontaktiert unse wenn ihr Fehler findet, damit wir möglicherweise falsch benotete Dokumente updaten oder entfernen können.
|
DE
Basket
