Activation of T Lymphocytes

dr. Widya Wasityastuti, M.Scwasityastuti@yahoo.com

Faculty of Medicine Universitas Gadjah Mada

2Development in primary lymphoid organs

Activation in secondary or peripheral lymphoid

organs

Outlines

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

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

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

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

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

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

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).

Activated dendritic cells from tissue meet nave T cells in T cells area of secondary lymphoid organs

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

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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