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T-Zell Rezeptor Signalweg

Der T-Zell Rezeptor (TCR) ist ein Proteinkomplex auf der Oberfläche von T-Zellen und dient der Erkennung von Antigenen. Durch Aktivierung wird eine Signalkaskade in Gang gesetzt die in der T-Zelle Differenzierung, Vermehrung und Ausschüttung von Cytokinen induziert.

Src-family Kinasen (SFKs1) Lck und Fyn phosphorylieren TCR ITAMs (immunoreceptor tyrosine-based activation motifs) im CD3 Komplex und ermöglichen Zap-70 so and ITAM zu binden. Phosphorylierung und Aktivierung wird durch den CD45 Rezeptor reguliert.2. Die Bindung bringt Zap-70 in Position seinerseits das transmembrane Protein Linker of activated T-Cells (LAT) zu phosphorylisieren.

SLP-76 und andere Signalproteine binden nun an LAT und werden ebenfalls durch ZAP-70 phosphoryliert4. SLP-76 begünstigt die Bindung von Vav(GEF), den Adaptorproteinen NCK und GADS und der T-Zellkinase (Itk). Itk aktiviert PLCγ1 was zur Hydrolyse von Phosphatidylinositol 4,5-bisphosphate (PIP2) führt, die beiden sekundären Messenger Diacylglycerol (DAG) und Inositol Trisphosphate (IP3) werden gebildet. DAG aktiviert PKC4 und den MAPK/Erk Signalweg wodurch die Transkriptionsfaktoren NF-κB und ATF2 aktiviert werden. IP3 induziert die Freisetzung von Ca2+ aus dem ER, was gleichzeitig die Aufnahme von extrazellulären Ca2+ Kationen mittels Calcium Release-activated Ca2+ (CRAC) Kanälen auslöst. Calmodulin-Kalzium Komplexe aktivieren die Phosphatase Calcineurin. Transkriptionsfaktor NFAT wird ebenfalls aktiviert und ermöglicht die Transkription von IL-2 im Zellkern.

Zur Verbesserung einer zielgerichteten Zellantwort werden die Signalkaskaden an mehreren Stellen reguliert. Extrazelluläre Signale nehmen durch Oberflächenrezeptoren wie CD28 oder LFA-1 zusätzlich Einfluss.


Literatur:

  • Liu Y (1999): “Protein kinase C activation inhibits tyrosine phosphorylation of Cbl and its recruitment of Src homology 2 domain-containing proteins.” J Immunol, 162(12):7095-101 [PMID: 10358153]
  • Wang HY (2001): “Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.” J Biol Chem, 276(28):26004-11. [PMID: 11353765]
  • Braiman, A and Isakov, N (2015): "The Role of Crk Adaptor Proteins in T-Cell Adhesion and Migration”. Front. Immunol., v.6,2015. [PMID: 4593252]
  • van Panhuys (2016): “CTCR Signal Strength Alters T–DC Activation and Interaction Times and Directs the Outcome of Differentiation.” Front Immunol, 7:6. [PMID: 26834747]
  • Courtney, AH (2017): “A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45.” Mol Cell , 3;67(3):498-511 [PMID: 28735895]
  • Tay A, Poh C et al. (2020): " The trinity of COVID-19: immunity, inflammation and intervention.” Nat Rev Immunol, 20(6):363-374. [PMID: 32346093]
  • Waldman AD, Fritz J, et al (2020): “A guide to cancer immunotherapy: from T cell basic science to clinical practice.” Nat Rev Immunol, 20(11):651-668 [PMID: 32433532]
  • Tarke A, Sidney J et al. (2021): “Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.”Cell Rep Med, 2(2):100204 [PMID: 33521695]


Receptor and Membrane Proteins

Stim2 (Stromal Interaction Molecule 2):

CD3G (CD3g Molecule, gamma (CD3-TCR Complex)):

CD3D (CD3d Molecule, delta (CD3-TCR Complex)):

HLA-DRB1 (Major Histocompatibility Complex, Class II, DR beta 1):

HLA-DRB3 (Major Histocompatibility Complex, Class II, DR beta 3):

HLA-DRB4 (Major Histocompatibility Complex, Class II, DR beta 4):

HLA-ABC (HLA-ABC):

LAT (Linker For Activation of T Cells):

HLA-A (Major Histocompatibility Complex, Class I, A):

HLA-DPA1 (Major Histocompatibility Complex, Class II, DP alpha 1):

HLA-DPB1 (Major Histocompatibility Complex, Class II, DP beta 1):

HLA-DQA1 (Major Histocompatibility Complex, Class II, DQ alpha 1):

HLA-DQA2 (Major Histocompatibility Complex, Class II, DQ alpha 2):

HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ beta 1):

HLA-DQB2 (Major Histocompatibility Complex, Class II, DQ beta 2):

HLA-DRB5 (Major Histocompatibility Complex, Class II, DR beta 5):

SHC1 (SHC (Src Homology 2 Domain Containing) Transforming Protein 1):

SLC25A20 (Solute Carrier Family 25 (Carnitine/acylcarnitine Translocase), Member 20):

TRAF6 (TNF Receptor-Associated Factor 6):

TMEM189 (Transmembrane Protein 189):

STIM1 (Stromal Interaction Molecule 1):

Adaptor Proteins and Regulators

GAB2 (GRB2-Associated Binding Protein 2):

GRAP2 (GRB2-Related Adaptor Protein 2):

GRB2 (Growth Factor Receptor-Bound Protein 2):

LCP2 (Lymphocyte Cytosolic Protein 2 (SH2 Domain Containing Leukocyte Protein of 76kDa)):

MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene 1):

NCK1 (NCK Adaptor Protein 1):

PAG1 (phosphoprotein Associated with Glycosphingolipid Microdomains 1):

PTPN11 (Protein tyrosine Phosphatase, Non-Receptor Type 11):

GEFs and PLCs (Ca2+ regulated)

CBL (Cas-Br-M (Murine) Ecotropic Retroviral Transforming Sequence):

CDC42 (Cell Division Cycle 42 (GTP Binding Protein, 25kDa)):

ORAI1 (ORAI Calcium Release-Activated Calcium Modulator 1):

PTEN (Phosphatase and Tensin Homolog):

PIPLC - Phosphoinositide-Specific phospholipase C:

RAP1A (RAP1A, Member of RAS Oncogene Family):

RASSF5 (Ras Association (RalGDS/AF-6) Domain Family Member 5):

RASGRP1 (RAS Guanyl Releasing Protein 1 (Calcium and DAG-Regulated)):

RASGRP2 (RAS Guanyl Releasing Protein 2 (Calcium and DAG-Regulated)):

SOS1 (Son of Sevenless Homolog 1):

STIM1 (Stromal Interaction Molecule 1):

TRPV6 (Transient Receptor Potential Cation Channel, Subfamily V, Member 6):

VASP (Vasodilator-Stimulated phosphoprotein):

Kinases

ZAP70 (zeta-Chain (TCR) Associated Protein Kinase 70kDa):

PDPK1 (3-phosphoinositide Dependent Protein Kinase-1):

DRB1 (Dopamine Receptor Binding 1):

FYN (FYN Oncogene Related To SRC, FGR, YES):

ITK (IL2-Inducible T-Cell Kinase):

INPP5D (Inositol Polyphosphate-5-Phosphatase, 145kDa):

LCK (Lymphocyte-Specific Protein tyrosine Kinase):

MAP3K14 (Mitogen-Activated Protein Kinase Kinase Kinase 14):

MAP3K7 (Mitogen-Activated Protein Kinase Kinase Kinase 7):

MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8):

MAP4K1 (Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1):

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PKC (Protein Kinase C):

RIPK2 (Receptor-Interacting Serine-threonine Kinase 2):

TAB2 (TGF-beta Activated Kinase 1/MAP3K7 Binding Protein 2):

AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1):

Transcription Factors

CARD11 (Caspase Recruitment Domain Family, Member 11):

IKBKB (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase beta):

IKBKG (Inhibitor of kappa Light Polypeptide Gene Enhancer in B-Cells, Kinase gamma):

NFKB1 (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells 1):

NFKBIA (Nuclear Factor of kappa Light Polypeptide Gene Enhancer in B-Cells Inhibitor, alpha):

RIP2 (ROP Interactive Partner 2):

UBE2V1 (Ubiquitin-Conjugating Enzyme E2 Variant 1):

UBE2N (Ubiquitin-Conjugating Enzyme E2N):

IFNB1 (Interferon, beta 1, Fibroblast):

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