Lecture6.ppt

Immunology BE433 Prof Christine Loscher Lecture 6 Antigen presentation to T cells T cell-mediated Immunity Summary • TCR recognise peptides bound to MHC on the surface of another cell – antigen presenting cell • CD8 cytotoxic T cells– MHC1 – cells infected with pathogens that live in the cytosol •...

Immunology BE433 Prof Christine Loscher Lecture 6 Antigen presentation to T cells T cell-mediated Immunity Summary • TCR recognise peptides bound to MHC on the surface of another cell – antigen presenting cell • CD8 cytotoxic T cells– MHC1 – cells infected with pathogens that live in the cytosol • CD4 helper T cells – MHC2 – cells infected with pathogens or products that live in vesicles • By using either MHC1 or 2 cell can activate the appropriate cell Figure 5-2 Figure 5-6 What is presented by MHC1? • Antigen fragments that bind MHC1 are typically derived from viruses that take over the cells biomachinery to make their own proteins – these proteins made in the cytosol • Also present peptides from membrane of virus glycoproteins in viral envelope – or secreted protein • EVASION – some virus have developed ways of interfering with MHC:peptide complex being expressed on cell surface - Herpes simplex virus – prevents transport of viral peptides into ER by a protein that inhibits TAP. - Adenoviruses – encode a protein that binds to MHC1 and retains them in the ER Figure 5-10 Movie What is presented by MHC2? • Pathogens that replicate inside membrane vesicles – proteins not accessible to proteosomes – proteases inside vesicle degrade them to peptides • Both MHC1&2 cannot pick up any peptides from extracellular fluid so T cells only work on infected cells and spare the healthy ones • A T cell recognises peptide bound by a particular variant of an MHC molecule – will not recognise that peptide bound to any other MHC – MHC restriction T cell-mediated immunity Journey of the T cell • Development in the thymus • Move in to circulation • Migrate into peripheral lymphoid organ • Return to blood • Naïve T cells – have not yet encountered their specific antigen presented by antigen presenting cell • To participate in adaptive immune response the naïve T cell must encounter antigen, proliferate and differentaite into cells that contribute to the removal of antigen – armed effector T cells Antigen presenting cells • Present antigen to T cells in the form of peptide:MHC complex • 1. Dendritic Cell (DC) – ingest antigen and present to T cell – activation – migrate to lymphoid tissue – express co-stimulatory molecules (second signal for T cell activation) • 2. Macrophage – can also express MHC and co-stim molecules but less powerful than DC • 3. B cells – can serve as APC • Once a T cell response has been initiated B cells and macrophages can become targets for armed effector cells Dendritic cell Co-stim Co-stim Peptide:MHC TCR Macrophage Naïve T cell B cell Effector T cell Armed effector T cell • 3 functional classes • 1. CD8 cytotoxic T cells – recognise peptides from intracellular pathogens that multiply in the cytosol - are degraded and associate with MHC1 • 2. CD4 helper T cell – recognise peptides from pathogens multiplying in vesicles and ingested pathogens and toxins boud to MHC2 • Th1 – pathogens that accumulate in large numbers in macrophage and DC – activate microbiocidal properties of macrophages and induce B cells to make IgG for opsonizing extracellular pathogens for phagocytosis • Th2 – extracellular antigens – can stimulate B cells to produce IgA and IgE aswell as neutralising subtypes of IgG Figure 8-1 Dendritic Cells • Most potent antigen presenting cell • Activated by the innate immune response and critical to initation of adaptive immune response • Ingest pathogens – phagocytosis, PRR • Migrate to lymph node – have lost ability to ingest anymore antigen • Present ingested antigen to T cells Figure 8-2 Figure 8-4 How do T cells get into lymphoid tissue? • The migration of naïve T cells through the lymph nodes and their initial interactions with APC depends on cell adhesion molecules – similar interactions guide the effector T cells into the peripheral tissues and are important in their interaction with target cells • T cells bind to endothelial venules – T cell has adhesion molecules that recognise adhesion molecules on the endothelial venules • T cells express L-selectin • This interacts with mucin-like molecule, CD34 and GlyCAM-1 – expressed as sialyl-LewisX molecules on endothelial venules • This interaction guides naïve T cells to lymph nodes Figure 8-5 part 1 of 2 How do T cells get into lymphoid tissue? • The chemokine CCL21 is expressed by vascular endo cells and binds CCR7 on naïve T cells • This interaction enhances intergrin affinity • LFA-1 found on T cells and ICAM-1 on endo cells • MOVIE (trafficking) Figure 8-6 part 1 of 3 The initial interaction of T cells with APC also mediated by adhesion molecules