7: Lymphocytes Flashcards
Adaptive immunity, immune memory, antigen receptor diversity, T cells, MHC, B cells, antibody function
Adaptive immunity
response of vertebrate immune system to a specific antigen that typically generates immunological memory
Cells involved in adaptive immunity
B cells
Antibodies
T cells
Natural killer T cell (also in innate immunity)
An adaptive immune response (AIR) is initiated when
a pathogen overwhelms innate defence mechanisms
pathogen replicates, antigen accumulates = sensor cells become activated to trigger AIR
Expansion of antigen-specific lymphocytes that target pathogen specifically, formation of memory cells providing long-lasting specific immunity
Role of adaptive immune system
- Improves efficacy of innate immune system
- Focuses a response on site of infection and organism responsible
- has memory
- needs time to develop
What major event occurs in peripheral lymphoid tissues to initiate adaptive immune responsse?
B or T lymphocytes encounter antigens for which receptors have specific reactivity
Antigen
molecules recognised by highly specialised lymphocyte receptors, which act to induce an adaptive immune response
2 hallmarks of adaptive immune response
- Creates immunological memory; long-lasting protection
- Highly specific : recognises non-self antigens
Issue with Specificity
antigen diversity - large number of lymphocyte receptors that can recognise array of antigens needed
10^15 different antibody/BCR molecules can be generated each coded by one gene = this isnt possible so immunoglobulin gene rearrangement occurs
Immunoglobulin gene rearrangement
Each BCR receptor chain encoded by separate multigene families on different chromosomes
During B cell maturation, gene segments rearranged and brought together
How is diversity generated overall?
Germline diversity
Combinatorial diversity
Junctional diversity
Heavy + light chain diversity
Germline diversity
Each gene segment consists of different base sequence
Combinatorial diversity
formation of different combinations of V, J and D segments from each cluster
Junctional diversity
addition/removal of random bases to form a viable junction between selected V, D and J segments
Heavy+light chain diversity
same heavy chain can be combined with different versions of a light chain (and vice versa)- many different combinations of heavy and light chain V regions that pair to form antigen-binding site in immunoglobulin molecule
Issues with the process of gene rearrangement
with many different receptors generated randomly during lifetime, possibility of self-reactive antibodies –> autoimmunity
Immunological memory
quicker response, producing antibodies
T cell response
Cell-mediated response
B cell response
Humoral/antibody response
Lymph node interactions of B cells
stay outside lymph node
- respond directly to antigens drained into the lymph node
Lymph node interactions of T cells
Interior to lymph node
3 Types of T cells
Antigen binds to receptor - cell proliferates and differentiates into :
Cytotoxic T cells
Helper T cells
Regulatory T cells
Cytotoxic T cells
kill infected cells or other intracellular pathogens bearing the antigen
Helper T cells
provide signals (specific cytokines) that activate other cell functions e.g B cell antibody production / macrophage killing engulfed pathogens
Regulatory T cells
suppress other lymphocyte activity
help limit possible damage of immune response
What molecule on T cell surface helps distinguish T helper and T killer cells
CD4 - helper
CD8- killer
Types of Th cells
Tfh
Th1
Th17
Th2
Treg (Th0)
Tfh cells
pro-antibody
B-cell support
Produce : IL-21
Th1 cells
pro-inflammatory
boost cellular immune response-
produce interleukins that promote B cell class switching
involved in macrophages and inflammation
Produce: Interferon Gamma, Tumour Necrosis Factor, IL-12
Th17 cells
pro-inflammatory
control bacterial and fungal infection, neutrophils
Produce: IL-17, IL-23, IL-6
Th2 cells
pro-allergic
involved in allergies and worms (parasites)
Boost multicellular response
Produce: IL-4,IL-5, IL-13
Treg (Th0) cells
anti-inflammatory
limit immune response /supress T cell response
Produce: IL-10, TGFbeta
By what pathway do T helper cells activate B cells
thymus dependent pathway
- release of cytokines cause B cell proliferation and differentiation (clonal selection + expansion) into plasma and memory B cells
How do CD8 T cells kill pathogens?
Release perforins and granzymes
How do CTLs initiate programmed cell death?
Cytotoxic T cells (CTL) kill targets by apoptosis (characterised by fragmentation of nuclear DNA)
CTL store perforin, granzymes, granulysin in cytotoxic granules- released after target recognition
Perforin molecules polymerise, form pores
Two ways T cells recognise foreign antigens
Interactions between MHC and T-cell receptors
Epitope / antigenic determinant
region recognised by T cell antigen receptor
- antigen broken down into peptide fragments
-epitope peptide binds to self molecule and MHC molecule
-T cell receptor binds to complex of MHC molecule and epitope peptide
Epitope is formed by
combination of MHC-II and part of antigenic protein
MHC stands for
Major Histocompatility Complex
Role of MHC
Recognises self and non-self
APC takes in foreign peptides and forms MHC, which allows for T cell selection
What is the difference between MHC-I and MHC-II
MHC-1 : all nucleated cells, single variable alpha chain and common B-microglobulin
MHC-2 : only on “professional” antigen presenting cells e.g Dendritic cells, macrophages, B lymphocytes
has 2 chains, alpha and beta
Describe the structure of MHC class I molecules
Consist of two polypeptide chains
An alpha chain noncovalently associated with smaller chain, B2-microglobulin
Complete MHCI has 4 domains, 3 formed from MHC-encoded alpha chain, one from B2-microglobulin
Folded a1 and a2 domains form walls of cleft on surface of molecule = peptide-binding cleft/groove
MHC molecules are highly polymorphic - major differences in allelic forms located in cleft= influences peptide binding
Describe the structure of MHC-II molecules
consists of a noncovalent complex of two chains, a and b both of which span membrane
peptide-binding cleft is formed by two domains from different chains, a1 and B1 domains
sites of major polymorphism in MHCII molecules located in peptide-binding cleft
How does MHCI interact with T cell receptors
Intracellular pathogen/antigen presented on MHCI binds to CD8 T cells in cytosol
CD8 cytotoxic T cell responsible for pathogen surveillance and cytolysis of somatic cells
How does MHCII interact with T cell receptors
Extracellular pathogen/antigen presented on MHCII binds to CD4 T cells in endosomes
CD4 cells differentiate into several subsets of effector T cells that have different immune functions
Process of MHCI recognition
- Virus infects cell
- Viral proteins synthesized in cytosol
- Peptide fragments of viral proteins bound by MHCI in ER
- Bound peptides transported by MHCI to cell surface
- Cytotoxic T cells recognise complex of viral peptide with MHCI and kills infected cell
How is MHC expressed
co-dominant expression
each person can have up to 6 of each gene if completely heterozygous
more than 17,000 MHC variants
Two properties of MHC making it difficult for pathogens to evade immune response
MHC is polygenic - several different MHCI and MHCII genes, so every person has a set of MHC molecules with different ranges of peptide-binding specificities
MHC is highly polymorphic - multiple variants/alleles of each gene within whole population
B cell antigen receptors
BCR - surface bound antibody
- encodes antibody the cell will make
BCR region of B cell
unique binding site which binds to antigenic determinant / epitope of antigen
Made before cell ever encounters antigen
Present in 1000s of identical copies on B cell surface
Two pathways by which antibody production by B cells is achieved
Thymus-dependent pathway
Thymus-independent pathway
Thymus dependent pathway
- membrane bound BCR recognises (thymus dependent) antigen
- receptor-bound antigen is internalised and degraded into peptides
-peptides associate with “self” molecules (MHC-2) and is expressed at cell surface - Complex recognised by matched CD4 T helper cell
- B cell activated (class switched, mature plasma/memory cell)
Thymus independent pathway
-some microbial antigens (thymus-independent antigens) activate B cells, in absence of helper T cells
-second signal triggered from direct recognition of common microbial constituent (LPS) = activating TLR signalling in B cell
-only IgM ; no memory produced
Thymus-independent antigens
highly repetitive molecules
can cross-link the BCR on B cells
e.g polysaccharides of bacterial cell walls
What happens once B cells undergo clonal selection
clonal expansion
Describe what is meant by clonal expansion of lymphocytes
1.foreign antigen interacts with receptor on mature naive lymphocyte, cell activated and divides
2. undergoes clonal expansion
3. antigen specificity maintained as cloned cells proliferate and differentiate into effector cells
5 types of antibodies produced by B cells
IgM
IgG
IgA
IgE
IgD
What is antibody type and function defined by
structure of its heavy chain
IgG
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Highest opsonisation and neutralisation acrivities
Classified into four subclasses - IgG1/2/3/4
lymphatic system
IgM
(5 Y star structure)
produced first upon antigen invasion, increase transiently
lymphatic system
IgA
(Two or 3 star Y structure)
expressed in mucosal tissues
forms dimers after secretion
small intestine, mouth, oesophagus
IgD
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unknown function
lymphatic system
IgE
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Involved in allergy
lymphatic system
Fab region of antibody
antibody region - varies between antibody types
Fc region of antibody
constant region
Describe the structure of the IgG antibody
Two heavy chains and two light chains
two heavy chains linked by disulphide bonds, each heavy chain linked to light chain by disulphide bond
Two identical antigen-binding sites
Two types of light chains, lambda and kappa, found in antibodies (never one of each)
3 core functions of antibodies
Neutralisation
Opsonisation
Complement activation
Neutralisation
antibodies bind to viruses/bacterial toxins and block access to cell they might infect or destroy
Opsonisation
antibodies coat bacterium to better enable phagocytic cells e.g macrophage/neutrophil to ingest and destroy it (Fc receptor on phagocytic cell binds to C receptor)
Complement activ
antibodies coat bacterial cell; C regions form platform that more efficiently activate complement proteins (covalent deposition on bacterial surface)–> complement proteins on bacterium can be recognised by complement receptors on phagocytes; stimulates phagocytes to ingest and destroy the bacterium
