T cell activation

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Response of CD4 T cells,What happens when a na ve T cell is activated. Proliferation,Cell cycle entry and cell division,Clonal expansion. Differentiation,Secretion of cytokines helper cells. Activation of killer functions cytotoxic cells,Acquisition of effector function. Important for down regulation of immune response, After activation T cells remain in lymph nodes for 5 6 days.
2 lymphoid organs bring cells of the immune system. Facilitate the complex cellular and molecular interactions. necessary to initiate the immune response,How do T cells and antigen meet in the lymph node. There are 3 types of professional antigen presenting cells Dendritic cells are by far the strongest. activators of naive T cells,Professional,Antigen Presenting. Dendritic cells,Note B cells are poor APCs,for primary naive T cells They. are selfish They really only,function as APCs in order to. direct activated antigen specific,T cells to provide them with.
Dendritic cells pick up antigen at sites of infection. The Dendritic Cell Paradigm and bring it to the regional lymph nodes or spleen. DC are present at all epithelial barriers where they are. sentinels for infection, DC ingest invading pathogens discriminate between self. vs non self, Upon this stimulus DC migrate to local lymph nodes. where they present pathogen antigens to T cells which. initiate specific immunity, Thus DC are critical for crosstalk between innate and. adaptive immunity,Immature dendritic cells,Immature dendritic cells. low expressors of MHC and costimulatory molecules,DCs in this state of maturation play a.
weak stimulators of T cells,predominant role in antigen capture from. within their local environments,highly endocytic,take up particles and microbes by phagocytosis. form large pinocytic vesicles in which extracellular fluid and. Immature DCs in the steady state are solutes are sampled a process called macropinocytosis. thought to mature spontaneously and express receptors that mediate adsorptive endocytosis. including Complement receptor C type lectin receptors as. acquire the capacity to induce T cell well as Fc receptors. C type lectins,DC maturation,Produced as transmembrane or secreted proteins. Highly conserved Carbohydrate Recognition Domain CRD. Binds sugars in a calcium dependent manner DC activators signals include proinflammatory. Mannosylation of peptide result in 100 to cytokines IL 1 GM CSF and TNF and bacterial or. 10 000 fold enhanced potency for T cell stimulation. viral products such as LPS CpG motifs and double,stranded RNA through TLR. Activated DCs can be distinguished from resting, mature DCs by expression of higher levels of MHC and.
costimulatory molecules or by production of cytokines. such as interleukin IL 12 and interferon, Dendritic cells undergo maturation to become Dendritic cells undergo maturation. potent antigen presenting cells in lymphoid tissue. Immature phenotype DCs,from bone marrow cultures,Intermediate phenotype 6 d. culture with GM CSF,Mature DCs Day 8 of culture,with GM CSF. Poor T cell activators Great T cell activators, I Mellman P Pierre and S Turley Nature 1997 388 787 792. DC maturation is associated with migration to the lymph node. Why are DCs such good APCs,1 The express both MHC class I and MHC class II.
2 They start in the right place tissues,3 They end up in the right place lymph node. 4 Immature DCs are highly efficient at taking up,antigens in the tissues. 5 After maturation and migration mature DCs present. these antigens to T cells in the lymph node,6 They express costimulatory molecules. Immature DC,Mature DC 21 22, Mature dendritic cells express key B7 molecules are ligands for CD28 on T cells. costimulatory molecules,B7 1 CD80 and B7 2 CD86,are structurally related.
glycoproteins expressed on,mature DCs,Collectively called B7. molecules they bind CD28 on, Naive T cells require two signals to become activated Remember how TCR signaling leads to IL 2 transcription. TCR MHC and costimulation,Protein tyrosine kinase,Phospholipase C Ras G proteins. Intracellular Ca2 Protein kinase C MAP kinases,The IL 2 gene. NF AT NF B AP 1 promoter,How does CD28 signaling enhance T cell activation.
CD28 signaling activates AP 1 and NF B,RECEPTOR CD28. CD28 signaling stabilizes IL 2 mRNA,Protein tyrosine kinase. Most cytokine mRNAs are very short lived,because of instability sequences in their 3. Phospholipase C Ras G proteins untranslated regions. MAP kinases Instability is important for tight regulation. Intracellular Ca2 Protein kinase C,CD28 signaling stabilizes IL 2 mRNA leading to a. 20 30 fold increase in protein secretion,The IL 2 gene.
NF AT NF B AP 1 promoter Stabilization combined with the activation of NF B. and AP 1 increases IL 2 secretion 100 fold,The costimulatory signal is necessary for. the synthesis and secretion of IL2 Summary I, Na ve T cells leave the thymus and home to secondary lymphoid. Dendritic cells are the most potent activators of na ve T cells. DCs carry antigen from the periphery to the draining lymph nodes. This migration is associated with maturation, Mature DCs express high levels of MHC as well as B7 costimulatory. B7 molecules bind CD28 on T cells CD28 signaling provides. Signal 2 to T cells and is necessary for T cell activation. CD28 costimulation is mediated in part by increasing IL 2. Why is costimulation necessary Lack of signal 2 leads to peripheral tolerance. Negative selection is not perfect,Some T cells will leave the thymus with. specificities for self antigens not expressed in,the thymus.
The requirement for costimulation ensures that T,cells will not be activated by cells expressing. these antigens, Peptides presented in the absence of costimulation. will not activate T cells 32,Signal 1 without Signal 2 leads to Anergy. Experimental evidence for signal 2,T cell Insulin,promoter HA. Activation Anti HA CD4,T cell clone,Anergy Anti HA TCR tg mouse HA tg mouse.
unresponsive Expresses HA in beta cells of the,state HA hemaglutinin an influenza virus protein. Experimental evidence for signal 2 Potentially self reactive cells are Anergic. Influenza infection normal immune response except no anti HA T cells produced. Double transgenic mouse,Insulin HA,Anti HA CD4,promoter Infect w Flu virus. Large numbers of anti HA CD4 T cells No response,T cell clone. HA expressed in the pancreas,T cells DCs HA,But no pancreatic infiltrate or diabetes. HA in pancreas,Strong response,Anti HA TCR tg mouse HA tg mouse T cells DCs.
X other Flu peptides,No response,T cells DCs HA,Potentially self reactive cells are ANERGIC 35 36. Summary II,Cross priming,Na ve T cells require 2 signals to be activated. 1 TCR To generate cytotoxic killer cells which have the capacity to eliminate. infected cells and attack transplants and tumour cells DCs have to. 2 CD28 costimulation, present antigenic peptides complexed to MHC class I molecules to. CD8 expressing T cells, Signal 1 in the absence of signal 2 leads to anergy. Straightforward if the DC is infected itself ie influenza virus. Anergic T cells are unresponsive to further stimulation. How DCs could process and present antigens that have no access. even in the presence of costimulation, to the cytosol in an MHC class I restricted manner for instance.
transplant and tumour derived antigens or antigens from viruses. Anergy is thought to be a mechanism of ensuring that cannot infect DCs. tolerance to peripheral antigens not expressed in the. Once the T cell response is started how is it turned off. Naive Memory, T cell activation is linked to signals that eventually. limit activation and remove most activated cells,CTLA 4 blocks costimulation. Fas induces apoptosis,T cell activation through TCR and CD28. CD28 and CTLA 4 leads to surface expression of CTLA4. CTLA 4 also expressed by T cells is a CD28 homologue. CD28 sends a positive co stimulatory signal enhancing T. cell activation,CTLA 4 sends an inhibitory signal, TCR CD28 signaling leads to upregulation of CTLA 4. CTLA 4 has a much higher affinity for B7 than does CD28. so it outcompetes CD28 for B7 binding,Antigen Induced Protein Translocation.
in 5C C7 T Cells,Manipulating signal 2,CD28 CTLA 4. CTLA 4 null mouse Dies of massive lymphadenopathy at several weeks. of age Idea is that there is nothing to counteract T cell activation. CD28 null mouse Hyporesponsive immune system but normal T cell. HB development, control antigen Transfect B7 into non APC and convert it into effective APC Consider. Green Tubulin implications for vaccine production, Blue Nucleus CTLA 4 Ig can inhibit immune responses consider mechanism and. potential uses, Anti CTLA 4 antibody can contribute to a more vigorous immune. specific antigen, Cancer regression and autoimmunity induced by CTLA4 blockade.
in patients with metastatic melanoma,Activated T cells also upregulate Fas. Activation,Na ve T cell,Both Fas and Fas ligand FasL are upregulated on. activated T cells, Signaling through Fas leads to activation of caspases and. programmed cell death apoptosis, Mutations in Fas or FasL lead to lympoproliferative and. autoimmune disorders,Fas signaling leads to programmed cell death.
One the T cell response is started how is it turned off. Figure 6 24,CTLA 4 puts on the brakes,by competing for B7 molecules and sending. inhibitory signals instead of activating,Fas gets rid of unwanted T cells. by inducing apoptosis in most of the,activated T cells after they do their job. Both of these signals are induced by the TCR,Summary III. Naive T cells leave the thymus and enter secondary. lymphoid organs, In secondary lymphoid organs na ve T cells are activated by.
mature dendritic cells, T cell activation requires 2 signals TCR and costimulation. Lack of costimulation during T cell activation leads to anergy. T cell responses are downregulated by CTLA 4 and Fas. CTLA4 competes for B7 binding,Fas induces apoptosis. 5 25 Naive T cells require two signals to become activated TCR MHC and costimulation How does CD28 signaling enhance T cell activation 26 RECEPTOR

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