Antigen recognition and activation of T-cells

Июль 31, 2022

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Antigen recognition and activation of T-cells

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2. T-cells can be distinguished from other lymphocyte types, such as B cells and NK cells by
3. Subsets of T cells: T helper cell (TH cells) assist other white blood cells in immunologic
4. TCR and CD3 complex ITAM - immunoreceptor tyrosine-based activation motifs
5. TCR co-receptors: CD4 – for Th (that is specific for class II MHC). CD8 – for
6. CD4 CD4 uses its D1 domain to interact with the β2-domain of MHC class II molecules.
7. CD8 The extracellular domain of CD8-α interacts with to the α3 portion of the Class I
8. T-cell activation The mechanism by which a T-cell elicits this response upon contact with its unique
9. Early signaling steps implicate the following molecules: Lck - Associated with the transmembrane tail of CD4
10. Lck (lymphocyte-specific protein tyrosine kinase) and Fyn are members of the Src family of tyrosine kinases.
11. Src (pronounced "sarc" as it is short for sarcoma) is a proto-oncogene encoding a tyrosine kinase
12. Structure of Src kinase P Binds to proline-rich region of proteins Binds to phosphotyrosines in proteins
15. In resting normal T-cells (a), Csk is present in lipid rafts through interaction with phospho-Tyr-317 in
16. SH2 and SH3 domains were found in several other protein families Kinases Phosphatases Phospholipases Adaptor proteins
17. ZAP-70 kinase ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 (70 is the molecular weight
18. 3D view of Zap-70
19. The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta Y P
20. ZAP-70 could phosphorylate the transmembrane protein LAT (linker of activated T cells). LAT localizes to lipid
21. Lipid raft The plasma membrane of cells is made of a combination of glycosphingolipids and protein
22. Sphingomyelin
23. T-cell signaling in lipid rafts
24. Human LAT is a 233 amino-acid type III transmembrane protein
25. A model of the signaling complexes assembled through LAT in T cells
26. “LAT signalosome”
27. LAT complexes. Balagopalan L et al. Cold Spring Harb Perspect Biol 2010;2:a005512 ©2010 by Cold Spring
28. LAT signaling complexes and microclusters. Balagopalan L et al. Cold Spring Harb Perspect Biol 2010;2:a005512 ©2010
29. Lymphoproliferative disease in LAT Y136F KI mice. Balagopalan L et al. Cold Spring Harb Perspect Biol
30. PLCγ PI3-K
31. PIP2 cleavage to IP3 and DAG initiates intracellular calcium release and PKC activation.
32. Protein kinase C also known as PKC activate PKC
33. Pleckstrin homology domain (PH domain) is a protein domain of approximately 120 amino acids can bind
34. PH domain
35. Mitogen-activated protein (MAP) kinases MAPKKK -> MAPKK -> MAPK -> Transcription factor
37. Guanine nucleotide exchange factor (GEF)
42. Скачать презентацию

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T-cells can be distinguished from other lymphocyte types, such as B

cells and NK cells by the presence of T cell receptors (TCR)

The TCR is a molecule found on the surface of T cells that is, in general, responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules

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Subsets of T cells:
T helper cell (TH cells) assist other white

blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages, among other functions (CD4+)
Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection (CD8+)
Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance (CD4+CD25+FoxP3+)
Natural killer T cells (NKT cells) are a special kind of lymphocyte that that recognize glycolipid antigen presented by a molecule called CD1d
γδ T cells (gamma delta T cells) represent a small subset of T cells (2% of total T cells) that possess a distinct T cell receptor (TCR) on their surface and rapidly respond to a set of non-peptidic phosphorylated isoprenoid precursors, collectively named phosphoantigens (isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP))
Memory T cells are a subset of antigen-specific T cells that comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells).

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TCR and CD3 complex
ITAM - immunoreceptor tyrosine-based activation motifs

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TCR co-receptors:
CD4 – for Th
(that is specific for class II

MHC).
CD8 – for CTL
(that is specific for class I MHC).

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CD4
CD4 uses its D1 domain to interact with the β2-domain of

MHC class II molecules.

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CD8
The extracellular domain of CD8-α interacts with to the α3 portion

of the Class I MHC molecule

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T-cell activation
The mechanism by which a T-cell elicits this response upon

contact with its unique antigen is termed T-cell activation

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Early signaling steps implicate the following molecules:
Lck - Associated with

the transmembrane tail of CD4
Fyn - Associated with ITAMs of the TCR complex
CD45 - The transmembrane tail of which functions as a Tyrosine phosphatase
Zap70 - Binds to ITAM sequences upon phosphorylation by Lck and Fyn

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Lck (lymphocyte-specific protein tyrosine kinase) and Fyn are members of the

Src family of tyrosine kinases.

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Src (pronounced "sarc" as it is short for sarcoma) is a

proto-oncogene encoding a tyrosine kinase originally discovered by J.Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine
This gene is similar to the v-src gene of Rous sarcoma virus
v-src lacks the C-terminal inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active

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Structure of Src kinase
P
Binds to proline-rich region of proteins
Binds to phosphotyrosines

in proteins

Could phosphorylate tyrosine residues

Could be phosphorylated

Binds to membrane

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In resting normal T-cells (a), Csk is present in lipid rafts

through interaction with phospho-Tyr-317 in Cbp/PAG.
This imposes a tonic inhibition of T-cell activation through Csk-mediated phosphorylation of the Lck regulatory site (Tyr-505).
Engagement of the TCR (b) results in dephosphorylation of Cbp by an unknown PTPase, dissociation of Csk from lipid rafts and displacement from its substrate Lck, leading to activation of Lck and allowing for initiation of the TCR-induced tyrosine-phosphorylation cascade.
However, after 2±5 min of activation (c), Cbp/PAG Tyr-317 is re-phosphorylated by Lck and/or Fyn thereby recruiting Csk back into lipid rafts.
this terminates Lck and Fyn activity and turns off TCR signalling.

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SH2 and SH3 domains were found in several other protein families
Kinases
Phosphatases
Phospholipases
Adaptor

proteins
Cytoskeleton proteins
Transcription factors etc.

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ZAP-70 kinase
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 (70

is the molecular weight in kDa).

The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta

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3D view of Zap-70

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The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated

ITAMs of CD3-zeta

ITAM
(D/ExxYxxL/Ix7YxxL/I)

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ZAP-70 could phosphorylate the transmembrane protein LAT (linker of activated T

cells).
LAT localizes to lipid rafts (also known as glycosphingolipid-enriched microdomains or GEMs) and acts as a docking site for SH2 domain-containing proteins
LAT has been shown to interact with SHB, PLCG1, GRAP2, ZAP-70, GRAP, Grb2, PIK3R1, ITK, MAP4K1 and VAV1.

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