Difference between revisions of "T cell differentiation"

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<big><center>[[Leukopoiesis - WikiBlood|'''BACK TO LEUKOPOIESIS''']]</center></big>
[[Image:TH1-2.jpg|thumb|right|200px|TH1 and 2 selection is influenced by infection - B. Catchpole, RVC 2008]]
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<big><center>[[Lymphoreticular System - Anatomy & Physiology|'''BACK TO LYMPHORETICULAR SYSTEM''']]</center></big>
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<big><center>[[Adaptive Immune System - WikiBlood|'''BACK TO THE ADAPTIVE IMMUNE SYSTEM''']]</center></big>
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==Introduction==
 
==Introduction==
[[T cells|T cells]] are long lived and are involved in '''cell mediated immunity'''. Functionally they are divided by the expression of CD4<sup>+</sup> or CD8<sup>+</sup> markers. CD4<sup>+</sup> T helper cells recognise antigens bound to MHC II complexes and are involved with the control of intracellular and extracellular pathogens; they can interact with CD8<sup>+</sup>, NK and dendritic cells or with B cells. Cytotoxic CD8<sup>+</sup> T cells recognise the MHC I complex and destroy infected or neoplastic cells.
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Within the blood and lymphoid organs the majority of [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T cells]] are antigen-naive T-cells. There is only a small proportion of memory T-cells.  
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Within the blood and lymphoid organs the majority of T cells are antigen-naive T cells; only a small proportion are memory T cells. Naive T cells have yet to encounter antigen and can only be activated by antigen that is presented by dendritic cells. After initial antigenic activation, naïve T-cells develop into an intermediate stage cell called the T<sub>H</sub>0 cell which can then be activated by any antigen-presenting cell, e.g. Dendritic cells, [[Macrophages|macrophages]] or [[B cells]].  
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Naive T-cells have yet to encounter antigen and can only be activated by antigen presented by dendritic cells. After initial antigenic activation, naïve T-cells develop into an intermediate stage cell called the TH<sub>0</sub> cell which can then be activated by any antigen-presenting cell, e.g. Dendritic cells, [[Macrophages - WikiBlood|macrophages]] or [[Lymphocytes - WikiBlood#B cells|B-cells]].  
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The TH<sub>0</sub> cells have the capacity to differentiate into TH<sub>1</sub> and TH<sub>2</sub> cells. The type of cell that develops depends on the antigen presenting cell. [[Macrophages - WikiBlood|Macrophages]] cause the TH<sub>0</sub> cell to develop into TH<sub>1</sub> cells caused by IL-12 production following [[Macrophages - WikiBlood|macrophage]]-antigen interaction. [[Lymphocytes - WikiBlood#B cells|B-cells]] cause the TH<sub>0</sub> cell to develop into TH<sub>2</sub> cells caused by IL-10 production following B-cell-antigen interaction. On antigenic stimulation the TH<sub>1</sub> or TH<sub>2</sub> cells become activated, undergo clonal expansion and secrete a range of different cytokines.
The T<sub>H</sub>0 cells have the capacity to differentiate into T<sub>H</sub>1, T<sub>H</sub>2 cells and a very recently described subtype T<sub>H</sub>17 cells. The type of cell that develops depends on the antigen presenting cell type. [[Macrophages|Macrophages]] cause the T<sub>H</sub>0 cell to develop into a T<sub>H</sub>1 cell induced by IL-12 production following macrophage-antigen interaction. B cells cause the T<sub>H</sub>0 cell to develop into a T<sub>H</sub>2 cell induced by IL-10 production following B cell-antigen interaction. On antigenic stimulation the T<sub>H</sub>1 or T<sub>H</sub>2 cells become activated, undergo clonal expansion and secrete a range of different cytokines. The third most recently described subset, T<sub>H</sub>17, form in the presence of IL-6 and TGF-β which are produced in the prescence of infection, and by either of the Antigen Presenting Cells (APCs). The importance of CD4<sup>+</sup> T<sub>H</sub> cells is very clear in immunity. An example of a disease that targets CD4<sup>+</sup> T cells is the Human Immunodeficieny Viruses (HIV) and Simian Immunodeficieny Viruses (SIV) which, when the CD4<sup>+</sup> T cells are overwhelmed, causes Advanced Immunodeficiency Syndrome (AIDS).  
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<br />
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For any one cell the cytokine-secreting activation state is short-lived, lasting between 4 - 40 hours. After this time these cells either die, or mature into the long-lived memory cells. The proliferation of [[Lymphocytes - WikiBlood#T cells|T cells]] continues until antigen disappears.
<br />
 
For any one cell the cytokine-secreting activation state is short-lived, lasting between 4 - 40 hours. After this time these cells either die or mature into the long-lived memory cells. The proliferation of [[T cells]] continues until the presentation of antigen ceases.
 
  
 
==Dendritic Cells==
 
==Dendritic Cells==
[[Image:Lineages of dendritic cells.jpg|thumb|right|300px|Diagram showing the 2 Lineages of dendritic cells - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 
There are two different lineages of dendritic cells:
 
*From myeloid precursor cells
 
*From plasmacytoid precursor cells
 
Dendritic cells stimulate a primary T cell response; they migrate through tissues, track to T cell dependent areas of the [[Lymph Nodes - Anatomy & Physiology|lymph nodes]] and cluster with the T cells. Dendritic cells have unique capabilities to take up antigen by pathways involving phagocytosis, macropinocytosis and clathrin-coated pits. The cell-surface antigen phenotype distinguishes the dendritic cell from [[Monocytes]]/macrophages and [[B cells]]. Their main function is priming T helper cells. They produce cell signaling cytokine molecules known as  [[Cytokines#Chemokines|chemokines]].
 
  
===Maturation signals===
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*Dendritic cells present antigen to [[Lymphocytes - WikiBlood#T cells|T cells]]
*Exogenous
 
**Bacteria or their products (LPS, LTA, lipoproteins)
 
**Viruses or their products (dsRNA, G-RSV)
 
**Protozoa or their products
 
**Helminths (SEA, ES 62)
 
*Endogenous
 
**Inflammatory mediators (IL-1/TNF&alpha;, hsp, FcR)
 
**Immune cells (CD40L, CD47, FasL)
 
[[Image:Maturation of Dendritic Cells.jpg|thumb|right|300px|Maturation of Dendritic Cells - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 
  
===Antigen Presentation===
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*Circulating monocytes differentiate to form immature dendritic cells called '''Langerhans Cells'''
Circulating [[Monocytes|monocytes]] differentiate to form immature dendritic cells called '''Langerhans Cells'''
 
  
Langerhans cells sample the tissue fluid by endocytosis:
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*Langerhans cells sample the tissue fluid by endocytosis
*Foreign organisms are internalised
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**Foreign organisms are internalised
* Within the dendritic cells, antigen is digested to peptides
 
* Some of the peptides formed bind to the cell’s [[MHC]] molecules
 
  
The Langerhans cells leave the epithelium and travel via the afferent lymph flow. They are now known as '''Veiled Cells'''. Veiled cells enter the paracortical region of the [[Lymph Nodes - Anatomy & Physiology|lymph node]] where they present antigen to the T cells. They are now known as '''Interdigitating Dendritic Cells'''.
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*The Langerhans cells leave the epithelium and travel via the afferent lymph. They are now called '''Veiled Cells'''
  
==T<sub>H</sub>1 Cells==
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*Veiled cells enter the paracortical region of the [[Lymph Nodes - Anatomy & Physiology|lymph node]] where they present antigen to [[Lymphocytes - WikiBlood#T cells|T cells]]. They are now called '''Interdigitating Dendritic Cells'''
[[Image:TH1-macrophage.jpg|thumb|right|200px|T<sub>H</sub>1 cells boost macrophage response - B. Catchpole, RVC 2008]]
 
TH<sub>1</sub> cells help macrophages digest bacteria - the organisms are contained in cellular vesicles.
 
  
T<sub>H</sub>1 cells secrete a range of cytokines, including:
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==TH<sub>1</sub> Cells==
* '''IL-2''', which induces proliferation of both [[Helper_CD4%2B#Helper_CD4.2B|CD4<sup>+</sup>]] and [[Cytotoxic_CD8%2B#Cytotoxic_CD8.2B|CD8<sup>+</sup> T-cells]]. This stimulation of T cell proliferation is the main function of the T<sub>H</sub>1 cell.
 
* '''Interferon gamma''' ('''IFN&gamma;''') which activates tissue macrophages and is the principal effector mechanism in the defence against intracellular bacteria and parasites such as  Mycobacteria, Brucella, Rickettsia Leishmania, Coccidia, and Babesia. IFN&gamma; activates macrophages and stimulates them to produce enzymes triggering intracellular killing mechanisms - specifically:
 
#Superoxide dismutase and myeloperoxidase that produce H<sub>2</sub>O<sub>2</sub> and trigger the "superoxide burst".
 
#Nitric oxide synthase which produces nitric oxide.
 
  
This is another example of the immune system working through the innate immune response, and this can even act to suppress antibody synthesis.
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*TH1 cells help macrophages digest bacteria (''organisms in vesicles'')
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* TH<sub>1</sub> cells secrete a range of cytokines.
 +
* Cytokines secreted include:
 +
** '''IL-2'''.
 +
*** Gives proliferation of both [[Lymphocytes - WikiBlood#Helper CD4+|CD4+]] and [[Lymphocytes - WikiBlood#Cytotoxic CD8+|CD8+ T-cells]].
 +
*** This stimulation of proliferation of [[Lymphocytes - WikiBlood#T cells|T cells]] is the main function of the TH<sub>1</sub> cell.
 +
** '''Interferon gamma''' ('''IFN&gamma;''').
 +
*** Activates tissue macrophages
 +
*** Is the principal effector mechanism in the defence against intracellular bacteria and parasites.
 +
**** E.g.  Mycobacteria, Brucella, Rickettsia (bacteria) and  Leishmania, Coccidia, Babesia (parasites).
 +
**** Activates macrophages and stimulates them to produce enzymes triggering the intracellular killing mechanisms, e.g.
 +
***** Superoxide dismutase and myeloperoxidase.
 +
****** Produce H<sub>2</sub>O<sub>2</sub> and trigger the "superoxide burst".
 +
***** Nitric oxide synthase.
 +
****** Produces nitric oxide.
 +
**** This is another example of the immune system working through the innate immune response.
 +
*** Can act to suppress antibody synthesis.
  
==T<sub>H</sub>2 Cells==
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==TH<sub>2</sub> Cells==
[[Image:TH2-Bcell.jpg|thumb|right|200px|T<sub>H</sub>2 cells incite increased antibody production - B. Catchpole, RVC 2008]]
 
T<sub>H</sub>2 cells help [[B cells]] produce antibody where the organism is present in tissue fluid. The T<sub>H</sub>2 population influences B cell activation, proliferation and immunoglobulin production. T<sub>H</sub>2 T cells also secrete a range of cytokines:
 
#'''IL-4''' which stimulates B cell growth and induces the heavy chain switch from [[Immunoglobulin M|IgM]] to [[Immunoglobulin G|IgG]] , [[Immunoglobulin A|IgA]] and [[Immunoglobulin E|IgE]], as well as proliferation of basophils and mast cells. IL-4 can inhibit some T cell responses.
 
#'''IL-5''' which activates B cells and stimulates a high rate of proliferation. IL-5 also promotes immunoglobulin synthesis and the proliferation and differentiation of eosinophils.
 
#'''IL-6'''  also activates B cells, stimulates a high rate of proliferation and promotes immunoglobulin synthesis.
 
  
==Common Functions of T<sub>H</sub>1 and T<sub>H</sub>2 Cells==
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*TH2 cells help [[Lymphocytes - WikiBlood#B cells|B cell]] produce antibody (''organism in tissue fluid'')
Both T<sub>H</sub>1 and T<sub>H</sub>2 cells produce IL-3 and granulocyte-macrophage colony stimulating factor ([[Leukopoiesis|GM-CSF]]). These act to activate and induce proliferation of [[Neutrophils|neutrophils]] and [[Macrophages|macrophages]]. [[Neutrophils|Neutrophils]] are the major phagocytic cells in the blood and the principal cells in acute inflammatory lesions whose function is chiefly the body's defence against extracellular bacteria. One of the major biological functions therefore of the activation of either T<sub>H</sub> subset is '''cytokine-controlled reactive [[Haematopoiesis - Overview|haematopoiesis]]'''.
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* The TH2 population influences [[Lymphocytes - WikiBlood#B cells|B cell]] activation, proliferation and immunoglobulin production.
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* The TH2 [[Lymphocytes - WikiBlood#T cells|T cell]] population secrete a range of cytokines.
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** '''IL-4'''
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*** Stimulates [[Lymphocytes - WikiBlood#B cells|B cell]] growth.
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*** Gives heavy chain switch from [[Immunoglobulin M - WikiBlood|IgM]] to [[Immunoglobulin G - WikiBlood|IgG]] , [[Immunoglobulin A - WikiBlood|IgA]] and [[Immunoglobulin E - WikiBlood|IgE]].
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*** Proliferation of basophils/ mast cells.
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*** Can inhibit some [[Lymphocytes - WikiBlood#T cells|T cell]] responses.
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** '''IL-5'''
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*** Activates [[Lymphocytes - WikiBlood#B cells|B cells]].
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*** Stimulates high rate [[Lymphocytes - WikiBlood#B cells|B cells]] proliferation.
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*** Promotes immunoglobulin synthesis.
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*** Proliferation and differentiation of eosinophils.
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** '''IL-6'''  
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*** Activates [[Lymphocytes - WikiBlood#B cells|B cells]].
 +
*** Stimulates high rate [[Lymphocytes - WikiBlood#B cells|B cell]] proliferation.
 +
*** Promotes immunoglobulin synthesis.
  
==T<sub>H</sub>17 Cells==
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==Common Functions of Th<sub>1</sub> and TH<sub>2</sub> Cells==
''Still under investigation''
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<br />
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* Both TH1 and TH2 cells produce IL-3 and granulocyte-[[Macrophages - WikiBlood|macrophage]] colony stimulating factor (GM-CSF).  
The T<sub>H</sub>17 cells form when T<sub>H</sub>0 cells are challenged with IL-6 and TGF-β to produce a number of cytokines that enhance the innate immune response <ref>{{citation|initiallast = Korn|initialfirst = T|2last = Bettelli|2first = E|3last = Oukka|3first = M|finallast = Kuchroo|finalfirst = V.K|year = 2009|jtitle = IL-17 and Th17 Cells|jor = Annual Reviews of Immunology|vol = 27|range = 485-517}}</ref>. The [[Cytokines|cytokines]] produced enhance the extravasation and chemotaxis of [[Neutrophils|neutrophils]] to the site of infection, in the aim of combating extracellular bacteria. These cytokines include:
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** These act to activate and induce proliferation of [[Neutrophils - WikiBlood|neutrophils]] and also [[Macrophages - WikiBlood|macrophages]].
*IL-17
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*** [[Neutrophils - WikiBlood|Neutrophils]] are the major phagocytic cells in the blood and  the principal cells in acute inflammatory lesions.  
*IL-17F
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**** Function chiefly in the defence against extracellular bacteria.
*IL-6
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** Therefore, one of the major biological functions of the activation of either TH subset is cytokine-controlled reactive [[Overview of Haematopoiesis - WikiBlood|haematopoiesis]].
*TNFα
 
*IL-21
 
*IL-22
 
*IL-23
 
Importantly they do not produce:
 
*IFNγ normally associated with T<sub>H</sub>1 cells
 
*IL-4 normally associated with T<sub>H</sub>2 cells
 
  
 
==Cytotoxic T-Cells==
 
==Cytotoxic T-Cells==
Cytotoxic T cells kill virus infected cells where the organisms are contained in the cell cytoplasm. Viruses are obligate intracellular pathogens that use the host cell machinery for pathogen protein synthesis; viral peptides associate with MHC class I and are expressed on the cell surface. [[T_cells#Cytotoxic_CD8.2B|CD8<sup>+</sup> cytotoxic T lymphocytes (CTL)]] recognise the antigen-MHC complex. Cytotoxic T-cells secrete a pattern of cytokines similar to that of TH<sub>1</sub> cells:
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*IFN&gamma; but not IL-2. The IFN&gamma; shifts the balance of the immune response in favour of TH<sub>1</sub> cells and there is therefore an increased level of T-cell proliferation. The initiation of the immune response via CTL leads to the selective proliferation of CTL which enhances the main mechanism of killing virally-infected cells.  
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*Cytotoxic T cells kill virus infected cells (''organisms in cytoplasm'')
 +
* Viruses are intracellular pathogens that use the host cell machinery for pathogen protein synthesis.
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** Viral peptides associate with MHC class I and are expressed on the cell surface.
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*** [[Lymphocytes - WikiBlood#Cytotoxic CD8+|CD8+ cytotoxic T-lymphocytes (CTL)]] recognise the antigen-MHC complex.
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* Cytotoxic T-cells secrete a pattern of cytokines similar to that of TH<sub>1</sub> cells.
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** I.e. IFN&gamma; but not IL-2.
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*** The IFN&gamma; shifts the balance of the immune response in favour of TH<sub>1</sub> cells.
 +
**** There is therefore an increased level of [[Lymphocytes - WikiBlood#T cells|T-cell]] proliferation.  
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***** The initiation of the immune response via CTL leads to the selective proliferation of CTL - enhances the main mechanism of killing of virally-infected cells.  
  
 
===Killing Mechanism===
 
===Killing Mechanism===
The CTl killing mechanism is initiated by direct CTL-target cell contact.   
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* The cells involved bind by antigen/[[MHC]] class I-TcR interaction. This allows the CTL's intracellular granules to be localised at the area of contact - the granules contain most of the molecules responsible for cytotoxicity.  
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* The CTl killing mechanism is initiated by direct CTL-target cell contact.   
* Direct cell contact stimulates the release of the granule contents into the area of contact between the two cells. The granules contain two groups of cytotoxic molecules.
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* The cells involved bind by antigen/MHC class I-TcR interaction.
#'''Perforin''', which is structurally related to the [[Complement|complement]] component, C9 and forms pores in the cell membrane.
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** This results in the CTL's intracellular granules becoming localised to the area of contact.
#'''Granzymes''', which are proteolytic enzymes that target cell nucleases and cause programmed cell death.
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*** These granules contain most of the molecules responsible for cytotoxicity.  
 +
* Direct cell contact stimulates the release of the granule contents into the area of contact between the two cells.  
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* The granules contain two groups of cytotoxic molecules.
 +
** Perforin.
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*** Structurally related to the [[Complement - WikiBlood|complement]] component, C9.
 +
*** Forms pores in the cell membrane.
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** Granzymes.
 +
*** Proteolytic enzymes.
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*** Target cell nucleases.
 +
*** Cause programmed cell death.  
  
 
==T-Cell Activation==
 
==T-Cell Activation==
T cells function only after recent activation by an antigen.
 
* CD4 binds MHC class II - [[T_cells#Helper_CD4.2B|CD4<sup>+</sup> T-cells]] recognise antigen only in association with [[Major Histocompatability Complexes#MHC II|MHC class II]].
 
* CD8 binds MHC class I - [[T_cells#Cytotoxic_CD8.2B|CD8<sup>+</sup> T-cells]] recognise antigen only in association with [[Major Histocompatability Complexes#MHC I|MHC class I]].
 
Activation of T cells requires two distinct signals:
 
* '''Signal 1''' is the interaction of the TcR with the antigenic peptide/[[Major Histocompatability Complexes|MHC]] complex on the antigen presenting cell.
 
*'''Signal 2''' is the interaction of CD28 on the T cells with its ligand, CD80, on the antigen-presenting cell (APC). APC expression of CD80 only occurs after the engagement of pattern recognition on Fc receptors or activation by the cytokines Interferon, IL-1&beta; or TNF&alpha;.
 
Signal 2 only occurs after the recognition of <font color=purple>DANGER</font>.
 
  
===Activation Scenarios===
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* [[Lymphocytes - WikiBlood#T cells|T cells]] function only after recent activation by antigen.
1. '''No signal 1''':
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* CD4 binds MHC class II.
:T cell is not activated as there is no antigen.
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** [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T-cells]] therefore recognise antigen only in association with MHC class II
2. '''Both signal 1 and signal 2'''
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* CD8 binds MHC class I.
:T cell is activated into clonal expansion and produces cytokines or becomes cytotoxic.  
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** [[Lymphocytes - WikiBlood#Cytotoxic CD8+|CD8+ T-cells]] recognise antigen only in association with MHC class I.  
3. '''Signal 1 but no signal 2'''
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* Activation of [[Lymphocytes - WikiBlood#T cells|T cells]] requires two distinct signals.  
:T-cell is triggered into apoptosis and dies.  
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** '''Signal 1'''
:This is the basis of "clonal deletion" and is a major mechanism of the development of tolerance. It ensures that T-cells do not react with self (non-dangerous) antigens.
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*** The interaction of the TcR with the antigenic peptide/MHC complex on the antigen presenting cell.  
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** '''Signal 2'''
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*** The interaction of CD28 on the [[Lymphocytes - WikiBlood#T cells|T cells]] with its ligand, CD80, on the antigen-presenting cell.  
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**** APC expression of CD80 only occurs after:
 +
***** The engagement of pattern recognition or Fc receptors.  
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***** Activation with cytokines.
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****** Interferons, IL-1&beta; or TNF&alpha;.
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**** Therefore '''signal 2 only occurs after the recognition of <font color=red>danger</font>'''.
  
===TCR Complex===
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===Scenarios===
[[Image:TCR Complex.jpg|thumb|right|250px|TCR Complex - Copyright Prof Dirk Werling DrMedVet PhD MRCVS]]
 
The T cell Receptor, or TCR is always associated with CD3, forming what is referred to as the '''TCR complex'''. TCR is expressed on the surface of T cells in a noncovalent association with a complex of transmembrane polypeptides.
 
  
CD3 contains 3 distinct polypeptide chains that are expressed exclusively on T cells: γ, ε, and δ. These molecules are members of the Ig superfamily - the ε chain associates with both γ and δ - and they play a 'chaperone' role in transporting newly synthesized TCR molecules to the cell surface.
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* '''No signal 1'''
CD3 also contains 2 identical chains: ζ and 16 kDa, which are found on T cells, macrophages and NK cells. Mice also can have an ε (eta) form.
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** [[Lymphocytes - WikiBlood#T cells|T cells]] is not activated as there is no antigen.
 +
* '''Both signal 1 and signal 2'''
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** [[Lymphocytes - WikiBlood#T cells|T cells]] is activated into clonal expansion.
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*** Produces cytokines or becomes cytotoxic.  
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** This is the response to a dangerous antigen.
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* '''Signal 1 but no signal 2'''
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** T-cell is triggered into apoptosis and dies.
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** This is the basis of "clonal deletion".
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*** A major mechanism of tolerance.  
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*** Ensures that T-cells do not react with self (non-dangerous) antigens.
  
 
===Response to Activation===
 
===Response to Activation===
The response of the T cells to obtaining Signals 1 and 2 is to express the receptor for the cytokine interleukin-2 (IL-2) and CD4<sup>+</sup> T-cells secrete IL-2.  
+
 
The final trigger for clonal expansion is the engagement of IL-2R with IL-2 from any activated CD4<sup>+</sup> T-cell. IL-2 produced by a CD4<sup>+</sup> cell may also stimulate clonal expansion of the CD4<sup>+</sup> cell.
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* The response of the [[Lymphocytes - WikiBlood#T cells|T cells]] to obtaining Signals 1 and 2 is:
 +
** To express the receptor for the cytokine interleukin-2 (IL-2).
 +
** In [[Lymphocytes - WikiBlood#Helper CD4+|CD4+ T-cells]] only, the secretion of IL-2.  
 +
* The final trigger for clonal expansion is the engagement of IL-2R with IL-2.
 +
** The IL-2 can come from any activated CD4+ T-cell.
 +
** IL-2 produced by a CD4+ cell may also stimulate clonal expansion of that cell.
  
 
==T-Helper Cell Function==
 
==T-Helper Cell Function==
[[Image:TH1-2.jpg|thumb|right|200px|TH1 and 2 selection is influenced by infection - B. Catchpole, RVC 2008]]
 
The function of T helper cells is to regulate the immune response. The cytokines they secrete exert their influence on other cell populations; most of the different effector cells of the immune system are affected by one or more of the cytokines secreted by T<sub>H</sub> cells.
 
  
TH cells secrete cytokines for only a short period after they have been activated; the range of cytokines that T<sub>H</sub> cells secrete after activation chiefly determines their function. Different T-helper cell subpopulations (T<sub>H</sub>1, T<sub>H</sub>2 and T<sub>H</sub>17 cells) secrete different sets of cytokines.
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* The function of T helper cells is to regulate the immune response.
 +
** The cytokines they secrete exert their influence on other cell populations.
 +
*** Most of the different effector cells of the immune system are affected by one or more of the cytokines secreted by TH cells.
 +
* TH cells secrete cytokines for only a short period after they have been activated.
 +
* The range of cytokines that TH cells secrete after activation chiefly determines their function.
 +
** Different T-helper cell subpopulations secrete different sets of cytokines.
 +
*** Th<sub>1</sub> and TH<sub>2</sub> cells.
 +
 
 +
==Links==
  
==References==
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[[B cell differentiation - WikiBlood|B Cell Development]]
<references />
 
<br><br>
 
{{Jim Bee 2007}}
 
  
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[[Lymphocytes - WikiBlood#Cytotoxic CD8+|Lymphocytes - WikiBlood]]
  
{{OpenPages}}
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[[Adaptive Immune System - WikiBlood#Structure and Function of MHC Class I|Major Histocompatability Complex (MHC) molecule]]
[[Category:Lymphocytes|E]]
 
  
[[Category:Adaptive Immune System|C]]
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<big><center>[[Leukopoiesis - WikiBlood|'''BACK TO LEUKOPOIESIS''']]</center></big>
 +
<big><center>[[Lymphoreticular System - Anatomy & Physiology|'''BACK TO LYMPHORETICUAR SYSTEM''']]</center></big>
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<big><center>[[Adaptive Immune System - WikiBlood|'''BACK TO THE ADAPTIVE IMMUNE SYSTEM''']]</center></big>

Revision as of 13:30, 28 August 2008

BACK TO LEUKOPOIESIS
BACK TO LYMPHORETICULAR SYSTEM
BACK TO THE ADAPTIVE IMMUNE SYSTEM


Introduction

Within the blood and lymphoid organs the majority of CD4+ T cells are antigen-naive T-cells. There is only a small proportion of memory T-cells.

Naive T-cells have yet to encounter antigen and can only be activated by antigen presented by dendritic cells. After initial antigenic activation, naïve T-cells develop into an intermediate stage cell called the TH0 cell which can then be activated by any antigen-presenting cell, e.g. Dendritic cells, macrophages or B-cells.

The TH0 cells have the capacity to differentiate into TH1 and TH2 cells. The type of cell that develops depends on the antigen presenting cell. Macrophages cause the TH0 cell to develop into TH1 cells caused by IL-12 production following macrophage-antigen interaction. B-cells cause the TH0 cell to develop into TH2 cells caused by IL-10 production following B-cell-antigen interaction. On antigenic stimulation the TH1 or TH2 cells become activated, undergo clonal expansion and secrete a range of different cytokines.

For any one cell the cytokine-secreting activation state is short-lived, lasting between 4 - 40 hours. After this time these cells either die, or mature into the long-lived memory cells. The proliferation of T cells continues until antigen disappears.

Dendritic Cells

  • Dendritic cells present antigen to T cells
  • Circulating monocytes differentiate to form immature dendritic cells called Langerhans Cells
  • Langerhans cells sample the tissue fluid by endocytosis
    • Foreign organisms are internalised
  • The Langerhans cells leave the epithelium and travel via the afferent lymph. They are now called Veiled Cells
  • Veiled cells enter the paracortical region of the lymph node where they present antigen to T cells. They are now called Interdigitating Dendritic Cells

TH1 Cells

  • TH1 cells help macrophages digest bacteria (organisms in vesicles)
  • TH1 cells secrete a range of cytokines.
  • Cytokines secreted include:
    • IL-2.
      • Gives proliferation of both CD4+ and CD8+ T-cells.
      • This stimulation of proliferation of T cells is the main function of the TH1 cell.
    • Interferon gamma (IFNγ).
      • Activates tissue macrophages
      • Is the principal effector mechanism in the defence against intracellular bacteria and parasites.
        • E.g. Mycobacteria, Brucella, Rickettsia (bacteria) and Leishmania, Coccidia, Babesia (parasites).
        • Activates macrophages and stimulates them to produce enzymes triggering the intracellular killing mechanisms, e.g.
          • Superoxide dismutase and myeloperoxidase.
            • Produce H2O2 and trigger the "superoxide burst".
          • Nitric oxide synthase.
            • Produces nitric oxide.
        • This is another example of the immune system working through the innate immune response.
      • Can act to suppress antibody synthesis.

TH2 Cells

  • TH2 cells help B cell produce antibody (organism in tissue fluid)
  • The TH2 population influences B cell activation, proliferation and immunoglobulin production.
  • The TH2 T cell population secrete a range of cytokines.
    • IL-4
      • Stimulates B cell growth.
      • Gives heavy chain switch from IgM to IgG , IgA and IgE.
      • Proliferation of basophils/ mast cells.
      • Can inhibit some T cell responses.
    • IL-5
      • Activates B cells.
      • Stimulates high rate B cells proliferation.
      • Promotes immunoglobulin synthesis.
      • Proliferation and differentiation of eosinophils.
    • IL-6
      • Activates B cells.
      • Stimulates high rate B cell proliferation.
      • Promotes immunoglobulin synthesis.

Common Functions of Th1 and TH2 Cells

  • Both TH1 and TH2 cells produce IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF).
    • These act to activate and induce proliferation of neutrophils and also macrophages.
      • Neutrophils are the major phagocytic cells in the blood and the principal cells in acute inflammatory lesions.
        • Function chiefly in the defence against extracellular bacteria.
    • Therefore, one of the major biological functions of the activation of either TH subset is cytokine-controlled reactive haematopoiesis.

Cytotoxic T-Cells

  • Cytotoxic T cells kill virus infected cells (organisms in cytoplasm)
  • Viruses are intracellular pathogens that use the host cell machinery for pathogen protein synthesis.
  • Cytotoxic T-cells secrete a pattern of cytokines similar to that of TH1 cells.
    • I.e. IFNγ but not IL-2.
      • The IFNγ shifts the balance of the immune response in favour of TH1 cells.
        • There is therefore an increased level of T-cell proliferation.
          • The initiation of the immune response via CTL leads to the selective proliferation of CTL - enhances the main mechanism of killing of virally-infected cells.

Killing Mechanism

  • The CTl killing mechanism is initiated by direct CTL-target cell contact.
  • The cells involved bind by antigen/MHC class I-TcR interaction.
    • This results in the CTL's intracellular granules becoming localised to the area of contact.
      • These granules contain most of the molecules responsible for cytotoxicity.
  • Direct cell contact stimulates the release of the granule contents into the area of contact between the two cells.
  • The granules contain two groups of cytotoxic molecules.
    • Perforin.
      • Structurally related to the complement component, C9.
      • Forms pores in the cell membrane.
    • Granzymes.
      • Proteolytic enzymes.
      • Target cell nucleases.
      • Cause programmed cell death.

T-Cell Activation

  • T cells function only after recent activation by antigen.
  • CD4 binds MHC class II.
    • CD4+ T-cells therefore recognise antigen only in association with MHC class II
  • CD8 binds MHC class I.
    • CD8+ T-cells recognise antigen only in association with MHC class I.
  • Activation of T cells requires two distinct signals.
    • Signal 1
      • The interaction of the TcR with the antigenic peptide/MHC complex on the antigen presenting cell.
    • Signal 2
      • The interaction of CD28 on the T cells with its ligand, CD80, on the antigen-presenting cell.
        • APC expression of CD80 only occurs after:
          • The engagement of pattern recognition or Fc receptors.
          • Activation with cytokines.
            • Interferons, IL-1β or TNFα.
        • Therefore signal 2 only occurs after the recognition of danger.

Scenarios

  • No signal 1
    • T cells is not activated as there is no antigen.
  • Both signal 1 and signal 2
    • T cells is activated into clonal expansion.
      • Produces cytokines or becomes cytotoxic.
    • This is the response to a dangerous antigen.
  • Signal 1 but no signal 2
    • T-cell is triggered into apoptosis and dies.
    • This is the basis of "clonal deletion".
      • A major mechanism of tolerance.
      • Ensures that T-cells do not react with self (non-dangerous) antigens.

Response to Activation

  • The response of the T cells to obtaining Signals 1 and 2 is:
    • To express the receptor for the cytokine interleukin-2 (IL-2).
    • In CD4+ T-cells only, the secretion of IL-2.
  • The final trigger for clonal expansion is the engagement of IL-2R with IL-2.
    • The IL-2 can come from any activated CD4+ T-cell.
    • IL-2 produced by a CD4+ cell may also stimulate clonal expansion of that cell.

T-Helper Cell Function

  • The function of T helper cells is to regulate the immune response.
    • The cytokines they secrete exert their influence on other cell populations.
      • Most of the different effector cells of the immune system are affected by one or more of the cytokines secreted by TH cells.
  • TH cells secrete cytokines for only a short period after they have been activated.
  • The range of cytokines that TH cells secrete after activation chiefly determines their function.
    • Different T-helper cell subpopulations secrete different sets of cytokines.
      • Th1 and TH2 cells.

Links

B Cell Development

Lymphocytes - WikiBlood

Major Histocompatability Complex (MHC) molecule

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