adaptive immune system

week 1 block 2 ctb

adaptive immune system components

cellular components

• B lymphocytes (including plasma cells)

• cytotoxic T lymphocytes (T_c)

• helper T lymphocytes (T_H)

• regulatory T lymphocytes (T_reg)

• APCs

• memory cells: B/T lymphocytes

humoral component:

• ABs (immunoglobulins, Ig- various classes)

T cells and B cells

B cells: secrete ABs (immunoglobulins, Ig)

T_C: specifically kill infected cells and some tumour cells

T_H: secrete cytokines

2 arms of adaptive immunity

• both B and T cells have receptors for specific antigens on the cell surface

• only one version of a receptor on each individual cell

• millions of different receptors in the population of cells

• antigen receptor on B cells is membrane-bound immunoglobulin

importance of the fact that there is onlt one specificity of receptor on any one cell

• can control which receptors are present by controlling cells

• can eliminate receptors of particular specificity by eliminating cells

• can produce more of the receptor by stimulating multiplication of the appropriate cells

B cell activation: plasma cells

• co-operation with T_H cells is required to activate B cells

• when correct antigen binds to antigen-receptor (surface Ig) on B cell surface, cell is activated and starts producing and secreting the same AB at a high rate

• each activated B cell and its progeny produces AB with one sort of antigen binding site

importance of cell signalling

• first step: binding of antigen to the surface Ig

• must change the behavious of the cell: activating it by changing gene expression

• signals must pass from plasma membrane to the nucleus: by phosphorylation of target proteins by kinases, changes in Ca, etc

• intra-cellular signalling pathways are important in controlling immune response

adaptive humoral immunity

• humoral immunity: aspects of immunity-mediated by molecules in extracellular fluid as opposed to cell-mediated immunity

• term often used to refer to AB-mediated immunit

AB binding to an antigen can:

• block a pathogen from causing harm

• opsonisation: mark a pathogen for phagocytosis

• activate complement system

multiple AB binding

• many different ABs can bind to separate parts of the same antigen known as epitopes

• some of these ABs will have higher affinity for antigen than others

• all usual inter-protein binding forces apply (charge interactions, hydrophobic interactions, etc) as well as shape complementarity

epitopes

• large molecules can have multiple structural features (epitopes) that act as antigenic determinants

• usually the molecule has different structural features

• for some molecules (eg polysaccharides), the same structure is present in multiple copies

clonal selection

• B cells producing the right AB are selected from a big range of B cells

• each stimulated B cell produces a clone of cells producing AB that binds the same antigen

• a particular antigen may activate hundreds of different clones

immunological memory

• selective stimulation of B cells recognising antigen means that the AB produces reacts specifically with that antigen

• can also be applied to T cells

• pathogen-reactive lymphocytes are therefore selectively expanded, resulting in increased immunity (can be long lasting)

• activated T_H are also needed for B cell activation

primary and secondary AB responses

• after antigen exposure, only small fraction of B cells will specifically recognise it 

• will be triggered to secrete their Ig (antibody)

• these cells also proliferate: some of the cells formed will persist and form memory cells

  • next time more cells recognise the antigen

• log scale: almost 100x as much AB can be produced in the secondayr response and more quickly

• specificity: different antigen injected later only produces the much smaller primary response

antibody classes

• IgG

• IgE

• IgM

• IgA

• IgD

AB class switching

• involves rare event: loss of DNA within genome very rarely occurs in any mammalian cells 

• lymphocytes use changes in their genomic DNA for generating different antigen-binding sites as well as class switching

T cell function

• T cells all possess receptors which have large range of specificites (like surface Igs - B cell antigen receptors)

• due to highly diverse AA sequences of the variable (antigen-binding) region

• 2 main types of T cell:

  • T_C : most of which have the cell surface protein CD8

  • T_H : most of which have the cell surface protein CD4

T_H cells

• T_H activate other cells, including B cells and macrophages, by cell-cell contact and by secreting cytokines

  • TH1 cells secrete cytokines (interferon γ) that mainly activate virally infected cells, macrophages and other T cells

  • TH2 cells secrete (interleukins) that mainly activate B cells

  • some CD4+ (Tregs) have inhibitory roles

cytotoxic T cells

• cytotoxic T cells are central to the cell-mediated arm of adaptive immunity

• almost all cell types can present antigen on MHCI molecules on their cell surface if infected

• when cytotoxic T cell recognises foreign antigen presented on MHCI molecules, it proliferates

  • T_H cells influence this process

• activated T_C cells produce the pore forming proteins perforn and granulysin, as well as granzymes (proteases)

  • causes apoptosis of the target cell

TCR (T cell receptor)

• TCRs are αβ heterodimers with each monomer about 280 AAs in size

• each of the monomers has 2 immunoglobulin-like domains, one variable and one constant

• variable domains contain complementarity-determining regions

• TCRs are associated with CD3 complex, which is involved in cell signalling

antigen presentation

• T cells won’t recognise antigens in solution: only peptides ingested, processed and presented on MHC complexes by other cells

MHC proteins

• MHC proteins were named from their crucial role in controlling transplantation rejection

• MHC proteins present antigens (foreign peptide) on cell surface

• T cell receptor on the surface of T cells interacts with both the antigen and the MHC protein presenting it

• MHC incompatibility leading to transplant rejection of unmatched tissue accounts for search for ‘compatible’ donors

• other interactions between APCs and T-cells do occur, but only the TCR/antigen/MHC interaction gives the high specificity

class I MHC proteins

• present on most cells

• recognised by CD8+ cytotoxic T cells

class II MHC proteins

• present on APCs

• recognised by CD4+ helper T cells

class I MHC protein structure

• MHCs are 4 domain αβ heterodimers

• in class I MHC, the β₂ microglobulin is an invariant chain non-covalently attached to the α chain

• binding site for the antigenic peptide is formed from 2 domains of the α chain

• peptides are derived from the cell cytoplasm

• peptides derived from cell cytoplasm may include those from proteins of intracellular viruses

class II MHC protein structure

• class II MHC protein is αβ heterodimers

• 2 similarly sized polypeptide chains

• overall domain structure has clear similarities to class I MHC

• the binding site for peptide antigens is formed from both chains combined

• peptides are derived from ingested material

CD4and CD8 accessory molecules

• CD4 and CD8 bind to non-variable parts of MHC proteins and promote interaction between T cells and target/presenting cells

• class I MHC presents antigens from within any cell (viral peptides from an infected cell) and is recognised by CD8+ cytotoxic T cells which will kill the infected cells

• class II MHC presents antigen ingested and processed by a macriohage, dendritic cells or B cells and stimulates CD4+ T_H cells

class I and class II MHC protein tables

MHC protein variability

• several hundred different allelic variants of class I and class II MHC molecules have been identified in humans

• encoded at MHC genetic locus, crucial to immune response

• capable of presenting an enormous array of peptides to T cells (their broad specificity is very different to high specificity of antigen binding to Ig/TCR)

• MHC molecules present in individuals do influence susceptibility to disease, presumably through different efficiencies in presenting peptides from pathogens)