MHC Presentation PDF

MHC and antigen presentation & T cell receptor and T cell activation Prof Palmer Pathogen molecule What do MHC proteins do? Bind to peptide fragments and Display/present them on the cell surface – like a barcode T cells interact with the MHC to look for evidence of ab...

MHC and antigen presentation & T cell receptor and T cell activation Prof Palmer Pathogen molecule What do MHC proteins do? Bind to peptide fragments and Display/present them on the cell surface – like a barcode T cells interact with the MHC to look for evidence of abnormal proteins on the cell (due to viral/bacterial invasion, cancer cells or foreign cells) MHC and functions Endogenous pathway Exogenous pathway Pathogen molecule T cell T cells help eliminate pathogens present in infected cells and also help B cells make better and different kinds of antibodies to protect against extracellular microbes and toxic molecules. To accomplish these important functions, T cells have to interact intimately with other cells and then find and instruct or eliminate the ones that are harboring or have been exposed to these pathogenic threats. However, T cells are unable to peek beneath the surface of cells to identify ones that have ingested bacteria or are synthesizing viral or mutant proteins. Instead, antigen presentation systems have evolved, that display on the cell surface information about the various antigens that cells are synthesizing or have ingested  These antigen presentation pathways monitor the major subcellular compartments wherein pathogens could be lurking and report their findings to the appropriate kinds of T cells. Endogenously synthesized antigens in the cytosol of all cells are presented to CD8+ T cells as peptides bound to MHC I molecules Thereby allowing the CD8+ lymphocytes to identify and eliminate virally infected cells or cancers Pathogen molecule ITAM = immunoreceptor tyrosine-based activation motif (recognized by Src kinases) ITAM = immunoreceptor tyrosine-based activation motif (recognized by Src kinases)  Antigens ingested into endocytic compartments of macrophages, dendritic cells or B cells are presented to CD4+ T cells as peptides bound to MHC II molecules. T cells have antigen receptors that recognize antigenic peptide, but only in the context of MHC I or MHC II molecules that are displaying the antigen on the cell surface. Consequently, T cells are directed to work with cells, while not being ‘distracted’ by free antigen, to which they would not be able to do anything. Moreover, the pattern of expression of MHC I and II molecules directs T cells to interact with exactly the right kind of cells. MHC I and II molecules present protein fragments to CD8+ and CD4+ T cells, respectively.  Negative selection of T cells in thymus Self antigen (found in thymus) Immune cells expressing random receptors on their surface Cell activation Cell death Self antigen Cell released from thymus or bone-marrow No activation Cell survives CD4 and CD8 – co-receptors of TCR CD4 structure Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily. It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell: D1 and D3 resemble immunoglobulin variable (IgV) domains. D2 and D4 resemble immunoglobulin constant (IgC) domains. The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in two β-sheets, in a Greek key topology CD4 interacts with the β2-domain of MHC class II molecules through its D1 domain. T cells displaying CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted). MHC class I contains Beta-2 microglobulin CD4 function CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. The TCR complex and CD4 bind to distinct regions of the antigen- presenting MHC class II molecule. The extracellular D1 domain of CD4 binds to the β2 region of MHC class II. The resulting close proximity between the TCR complex and CD4 allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4[ to phosphorylate tyrosine residues of immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3 to amplify the signal generated by the TCR. Phosphorylated ITAMs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK), such as ZAP70, to further mediate downstream signalling through tyrosine phosphorylation. These signals lead to the activation of transcription factors, including NF- κB, NFAT, AP-1, to promote T cell activation CD4 signal cascade CD8 co-receptor for TCR To function, CD8 forms a dimer, consisting of a pair of CD8 chains. The most common form of CD8 is composed of a CD8-α and CD8-β chain, both members of the immunoglobulin superfamily with an immunoglobulin variable (IgV)-like extracellular domain connected to the membrane by a thin stalk, and an intracellular tail. CD8 co-receptor for TCR in CD8+ cells CD8 function The extracellular IgV-like domain of CD8-α interacts with the α3 portion of the Class I MHC molecule. This affinity keeps the T cell receptor of the cytotoxic T cell and the target cell bound closely together during antigen-specific activation. Cytotoxic T cells with CD8 surface protein are called CD8+ T cells. The main recognition site is a flexible loop at the α3 domain of an MHC molecule. This was discovered by doing mutational analyses. In addition to aiding with cytotoxic T cell antigen interactions the CD8 co-receptor also plays a role in T cell signaling. The cytoplasmic tails of the CD8 co-receptor interact with Lck (lymphocyte-specific protein tyrosine kinase). Once the T cell receptor binds its specific antigen Lck phosphorylates the cytoplasmic CD3 and ζ-chains of the TCR complex which initiates a cascade of phosphorylation eventually leading to activation of transcription factors like NFAT, NF-κB, and AP-1 which affect the expression of certain genes. B7 –CD28 – co-stimulation The classical two-signal hypothesis posited that both antigen and secondary stimuli are required for T cell activation The identification of the co-stimulatory receptor CD28 and a ligand, B7-1, With the subsequent identification of a co-inhibitory receptor (cytotoxic T lymphocyte antigen 4 (CTLA4), which also binds to B7-1) and a second ligand (B7-2, which binds to both CD28 and CTLA4), the two-signal model had already begun to evolve into a more complex regulatory system CD28 is constitutively expressed on the cell surface of naive CD4+ and CD8+ T cells, and provides an essential co-stimulatory signal for T cell growth and survival upon ligation by B7-1 and B7-2 on antigen-presenting cells (APCs). CTLA4 is induced following T cell activation and suppresses T cell responses When CTLA4 is upregulated, CD28 expression is subsequently downregulated by endocytosis48. Expression of B7-1 and B7-2 is modulated by the activation state of the APC. B7-2 is constitutively expressed on APCs at low levels, and infection, stress and cellular damage recognition by innate receptors activate APCs and induce transcription, translation and transportation of both B7-1 and B7-2 to the cell surface120,121. Therefore, the modulation of both receptors and ligands on T cells and APCs, respectively, provides multiple levels of regulation for T cell activation to promote T cell responses against non-self antigens while preventing or limiting aberrant and autoreactive T cell responses. IDO, indoleamine 2,3-dioxygenase.