4.5 - Lymphocytes

Question 1

White blood cell types

Answer 1

Innate immune cells:

• macrophages - eats stuff
• neutrophil - kills stuff

Adaptive immune cells - lymphocytes:

• T cell - orchestrates immune response / kills infected cells
• B cell - makes antibody

Question 2

Adaptive immunity

Answer 2

• improves efficacy of innate immune response
• focuses a response on the site of infection and the organism possible
• has memory
• needs time to develop
• specific and can differentiate within families
• absence of adaptive immunity results in inability to clear infections
• protects us from repeat infections with the same pathogens
• not without costs - autoimmunity

Question 3

Immunological memory

Answer 3

• once the immune system has recognised and responded to an antigen, it exhibits memory
• memory responses characterised by a more rapid and heightened immune reaction that serves to eliminate pathogens fast and prevent diseases
• reduction in severity on re-exposure
• antigen-specific lymphocytes (T and B) are the cellular basis
• basis for vaccines

Question 4

Types of adaptive immune response

Answer 4

T cells - cell mediated response

• produce cytokines to help shape immune response (CD4)
• kill infected cells (CD8)

B cells - humoral response

• produce antibodies

Question 5

Antigens

Answer 5

• antigens are molecules that induce an adaptive immune response (mostly proteins)
• antigens are how the adaptive immune system sees pathogens
• epitope: the region of an antigen which the receptor binds to
• T cells recognise linear epitopes in the context of MHC: cells can chop up proteins into fragments, which the MHC can display –> recognised by T cells
• antibodies recognise structural epitopes - recognise the tertiary structure of a protein

Question 6

Cell mediated response

Answer 6

• involves mostly T cells and responds to any cell that displays unusual MHC markers, including cells invaded by pathogens, tumour cells or transplanted cells

1. APCs displaying foreign antigens bind to T cells
2. interleukins (secreted by APCs or helper T cells) costimulate activation of T cells
3. if MHC-1 and endogenous antigens are displayed on the plasma membrane, T cells proliferate, producing cytotoxic T cells. If MHC-II and exogenous antigens are displayed on the plasma membrane, T cells proliferate, producing helper T cells
4. helper T cells release interleukins (and other cytokines), which stimulate B cells to produce antibodies that bind to the antigens, and stimulate nonspecific agents (NK and macrophages) to destroy the antigens

Question 7

Humoral response

Answer 7

• controlled by activated B cells and antibodies
  1. antigens bind to B cells
  2. interleukins or helper T cells costimulate B cells (usually both antigen and costimulator needed to activate B cell and initiate proliferation)
  3. B cells proliferate and produce plasma cells which bear antibodies with the identical antigen specificity as the antigen receptors of the activated B cells
  4. antibodies are released and circulate through the body, binding to antigens
  5. B cells produce memory cells (secondary response)

Question 8

Clonal expansion

Answer 8

• each lymphocyte bears a single, unique receptor
• interaction between a foreign molecule and that receptor leads to activation and clonal expansion (multiple copies of the same cell)
• differentiated effector cells of that lineage will bear the same receptor

Question 9

The problem of antigen diversity

Answer 9

• we are exposed to a large amount of different microbes and other antigenic determinants - immune system must be able to respond to all
• but - adaptive immune system is highly specific = to respond to all these different antigens, we need to have a very large pool of cells with specific receptors that can recognise these huge array of antigens
• we need to encode a massive repertoire of lymphocyte receptors
• each antibody is produced by a specific B lymphocyte expressing a specific BCR
• clonal selection: each lymphocyte bears a single, unique receptor; a specific antigen only activates its counter-specific cell, which then induces that particular cell to multiply, producing identical clones for antibody production
• generated through recombination
• 10^15 different antibodies, only 25000 genes

Question 10

Immunoglobulin gene rearrangement

Answer 10

• functional genes for antigen receptors do not exist until they are generated during lymphocyte development
• each BCR receptor chain (kappa, lambda and heavy chain genes) is encoded by separate multigene families on different chromosomes
• during B cell maturation these gene segments are rearranged and brought together
• this process generates the diversity of the lymphocyte repertoire

Question 11

T cell receptor

Answer 11

• part of a complex of proteins on the cell surface
• the variable region is made by gene reassortment
• recognises antigen fragments presented by other cells in the context of MHC
• components: carbohydrates, variable region, constant region, cytoplasmic tail (through transmembrane), disulphide bond between alpha and beta chain (if class II)

Question 12

The major histocompatibility complex

Answer 12

• plays a central role in defining self and non-self
• presents antigens to T cells
• critical in surgery and donor matching
• in humans, MHC is encoded by HLA genes
• the MHC is polygenic - several class I and II loci
• expression is codominant (maternal and paternal genes both expressed)
• MHC class I - all nucleated cells, although at various levels during infection / by cytokines. Has a single variable alpha chain plus a common beta-microglobulin. Communicates with CD8 cells
• MHC class II - normally only on professional APCs. Has two chains - alpha and beta. May be regulated by cytokines. Communicates with CD4 cells

Question 13

MHC / TCR interactions

Answer 13

intracellular pathogen/antigen –> processed in cytosol –> presented on MHC I –> presented to CD8 T cells (cytotoxic / killer cells)

extracellular pathogen/antigen –> processed in endosomes –> presented on MHC II –> presented to CD4 T cells (helper cells)

Question 14

CD4 T helper cell classes

Answer 14

• T helper cells produce cytokines (a family of inflammatory mediators)
• cytokines have diverse actions on a wide range of cells
• cytokines influence the outcome of the immune response
• Treg (Th0) - anti-inflammatory, limits the immune response
• Th1 - pro-inflammatory, boosts cellular immune response
• Th2 - pro-allergic
• Tfh - pro-antibody
• Th17 - pro-inflammatory, controls bacterial and fungal infection

Question 15

CD8 (cytotoxic T lymphocytes)

Answer 15

• kill their targets by apoptosis / programmed cell death
• apoptosis is characterised by the fragmentation of nuclear DNA
• CTL store perforin, granzymes, granulysin in cytotoxic granules released after target recognition
• perforin molecules polymerise and form pores
• CD8 cells detect non-self MHC and attacks, killing any infected cells

Question 16

Antibodies

Answer 16

• produced mainly by plasma cells
• used by the immune system to neutralise pathogens like viruses
• recognises antigen via the fragment antigen-binding (Fab) variable region
• each tip of the ‘Y’ of the antibody contains a paratope that is specific for one particular epitope
• two heavy and two light chains joined by disulphide bonds, constant region (interacts with other cells, functional part of molecule), variable region (specificity), hinge region
• 3 core protective roles: neutralisation (prevents bacterial adherance), opsonisation (promotes phagocytosis), complement activation (enhances opsonisation and lyses some bacteria)

Question 17

Antibody classes

Answer 17

• IgG - highest opsonisation and neutralisation, classified into four subclasses (1-4)
• IgM - 5 joined together in ring, produced first upon antigen invasion, increases transiently
• IgA - 1/2/3 units, expressed in mucosal tissues, forms dimers after secretion
• IgD - unknown function
• IgE - involved in allergy

Question 18

B cells

Answer 18

• B cell generation and maturation occur in the bone marrow in the absence of antigen
• derived from stem cells in bone marrow
• migrate into circulation (blood, lymphatic system) and into lymphoid tissues
• mature B cells specific for particular antigen
• specificity resides in BCR for antigen

Question 19

B cell receptor

Answer 19

• surface bound antibody - encodes the antibody the cell will make
• BCR have a unique binding site which bind to a portion of the antigen called the epitope / antigenic determinant
• made before the cell ever encounters the antigen
• is present in thousands of identical copies on the surface of the B lymphocyte
• B cells bind soluble antigen
• has a light and heavy chain
• each is encoded by an individual gene, which is made by recombination of building blocks
• occurs in bone marrow before B cell is released

Question 20

Antibody production by B cells

Answer 20

• naive antigen-specific lymphocytes (B / T) cannot be activated by antigen alone
• naive B cells require accessory signal:
  1. directly from microbial constituents (thymus-independent, only IgM, no memory)
  2. from a T helper cell (thymus-dependent, all Ig classes, memory)

Question 21

Thymus-independent antigens

Answer 21

• directly activates B cells without help of T cells
• often polysaccharide, needs to have repetitive structure e.g. bacterial surface sugars
• the second signal is provided by a microbial PAMP e.g. LPS (or by an accessory cell)

Question 22

Thymus-dependent pathway

Answer 22

1. membrane bound BCR recognises antigen
2. receptor-bound antigen is internalised and degraded into peptides
3. peptides associate with ‘self’ molecules (MHC class II) and is expressed at the cell surface
4. this complex is recognised by matched CD4 T helper cell
5. B cell activated