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DESCRIPTION
nTRANSCRIPT
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Activation of T Lymphocytes
dr. Widya Wasityastuti, [email protected]
Faculty of Medicine Universitas Gadjah Mada
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2Development in primary lymphoid organs
Activation in secondary or peripheral lymphoid
organs
Outlines
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Outlines:
Structure of the T lymphocyte receptor
T lymphocyte development in the thymus Positive and negative selection on T lymphocytes
Mature T lymphocytes migrate to secondary lymphoid organs
T cell activation by antigen presenting cells Differentiation of T lymphocytes effector cells
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STRUCTURE OF T CELL RECEPTOR
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T cells
Membrane bound protein with single antigen binding site
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TCR Complex
Complete functional receptor complex contains : heterodimers associated with the six invariant accessory chains - signalling protein [a complex of four other signaling chains -two , one , one -collectively called CD3 and a homodimer of chains]
ITAM (Immunoreceptortyrosine based activation motifs)
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T CELL DEVELOPMENT
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Mature T cells
Immature T cells
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Thymus
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T cell development in Thymus
Generation of T cell receptors
Somatic gene rearrangements (recombination)
Expression of receptors in the cell surface
Selection of useful cells
Positive selection
Negative selection
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The TCR - and -chain genes are composed of discrete segments that are joined by somatic recombination during
development of the T cell
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The germline organization of the human T-cell receptor and loci generated by gene segment rearrangement-
assembly antigen specificity
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The numbers of human T-cell receptor gene segments and the sources of T-cell receptor diversity
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Proliferation of T cell precursor and somatic gene rearrangement occur in the cortical region of the thymus
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Double negative
thymocytesDouble positive
thymocytes
T cell receptor CD4+ CD8+
T cell receptor -CD4- CD8-
Failure in gene rearrangement will trigger apoptosis
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Selection of useful cells: positive selection in the thymic cortex
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Aims: to test whether TCR properly interact with self MHC
molecules expressed in the surface of thymic epithelial cells
Thymic epithelial cell
Thymic epithelial cell
No interaction die
Interaction survive and become single
positive thymocytes
CD4+ OR CD8+
Double positivethymocytes
Cortical epithelial cells (stromal cells) express high levels of MHC-I and MHC-II.
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Double positive thymocytes
Single positivethymocytes
T cell receptor CD4+ OR CD8+
T cell receptor CD4+ CD8+
Selection of useful cells: positive selection in the thymic cortex
Single positivethymocytes
Double positivethymocytes
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Selection of useful cells: negative selection in the thymic medulla
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Aims: to test whether TCR can recognize self molecules presented
by MHC molecules in the surface of thymic medullary APC
Medullary APC expressing self molecules
Interaction die (removal of self reactive cells)
No interaction survive
Single positivethymocytes
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Somatic gene rearrangement
Positive selection
Negative selection
Nave CD4+/CD8+ T cells (MHC restricted and self tolerant) pass out the thymus to blood stream through venule or lymphatic vessels
Apoptotic cells are removed by macrophages
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Summary: T cell development in Thymus
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Nave lymphocytes enter secondary lymphoid organs from blood
There are T cells area in the secondary lymphoid organsparacortex area in lymph nodesinterfollicular area in MALTperiarteriolar lymphoid sheet (PALS) in spleen
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Cellular traffic is orchestrated by chemotactic cytokines (chemokines) and adhesion molecules which direct nave T cells out the blood and into
lymphoid organs (Lnn, Spleen, Malt).
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Activated dendritic cells from tissue meet nave T cells in T cells area of secondary lymphoid organs
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APCs deliver three kinds of signals for the clonal expansion and
differentiation of naive T cells20
Three signals are needed to activate T cells
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Multiple signaling pathways convergence on the IL-2 promoter
NFAT (Nuclear factor of activated T cell), AP-1 (transcription factor)& NF B (transcription factor) is to act together to stimulate IL-2 transcription
proliferation & differentiation of T cells22
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Antigen recognition in the absence of co-stimulation leads to functional inactivation or clonal deletion of peripheral T cells
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Various forms of signal 3 induce the differentiation of nave CD4 T cell to several distinct types of effector function
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Effector T cells enter blood circulation and migrate to infected tissue
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CD4+ helper T cells
Infected tissue
CD8+ cytotoxicT cells
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Activation signals should be stopped:
Negative feedback of TCR signaling
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Developmental Phase Activation and Action Phase
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Interfolliculer area
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