T/B cell activation, differentiation and memory Flashcards
How is the adaptive immune response initiated?
= by the interaction between a naive T cell and an antigen presenting cell (APC)
= APCs have been activated by their PRRs at site of infection
= processed antigen has been presented as peptides on their surface in the groove of the MHC class I and II molecules
= same time they have migrated from tissues to a draining lymph node / spleen
What are the stages of T cell activation and differentiation? (summary)
Antigen recognition
Activation
Clonal Expansion
Differentiation
Effector functions
What is T cell recirculation?
Naive T cells continually recirculate between the blood, lymphatics and secondary lymphoid tissues
= when T cell enters lymph node = it browses the cells for APCs expressing a MHC-peptide that it can bind to
= this increases probability of T cell finding its specific antigen
= if T cell does find an APC expressing a MHC-peptide that it can bind to
= will initiate activation of the T cell
How are T cells activated?
= the two-signal hypothesis
Costimulatory signals are required for optimal T-cell activation and proliferation
Signal 1
= interaction of the TCR-CD3 complex with an MHC-peptide
Signal 2
= co-stimulation signal via CD28
Signal 3
= soluble cytokines
Successful T cell-APC interactions
= organise signalling molecules into an immunological synapse
What are some co-stimulatory receptors?
Several co-stimulatory receptors and ligands have been described:
Positive receptors
= e.g. CD28 and ICOS
= CD28 interacts with CD80/CD86 on APC = initial T cell activation
= ICOS interacts with ICOS-L on APC = effector and memory T cells
(ICOS is important in maintaining the activity of differentiated T cells)
Negative receptors
= e.g. CTLA-4, PD1 and BTLA
= CTLA-4 also interacts with CD80/86 on APC
(important in downregulating T-cell responses)
What does absence of co-stimulation lead to?
= Anergy
Two signals = T cell activation
MHC recognition in absence of co-stimulation (signal 2) = Anergic T cell
MHC recognition with negative co-stimulation = Anergic T cell
What are some examples of Antigen-Presenting Cells?
e.g. Dendritic cells, Macrophages and B lymphocytes
Different types of APCs have different properties
e.g. Dendritic cells
= best at activation naive T cells
All 3
= can activate effector cells and memory cells
EXTRA READING:
B cells
= internalise antigens via BCRs
= constitutively express MHC class II molecules + antigen presenting machinery
= express costimulatory molecules following activation
DCs + Macrophages
= phagocytic
= express receptors for apoptitic cells, DAMPs and PAMPs
= localise to T-cell zone of lymph nodes following activation
= constitutively express MHC class I molecules + antigen presenting machinery
= express co-stimulatory molecules following activation
= variety of subtypes, some migrating, some resident, some better at cross-presenting
= specific subtypes may specialise in activating different T cells
What are Superantigens?
= Certain antigens are able to bypass normal rules for TCR antigen specificity
= Superantigens can simultaneously bind to Vβ regions of TCRs / the α chains of MHC class II
= Disease related to exogenous superantigens include Toxic Shock Syndrome, food poisoning, scalded skin syndrome
= Polyclonal T-cell activation and dramatic cytokine release
What occurs during T cell differentiation?
= activation of a naive T cell increases secretion of IL-2 and its receptor IL-2R
= promotes differentiation of CD4+ T cells into effector T cells (Th1, Th2. Tregs)
= can also (depending on cytokines) differentiate CD8+ into cytotoxic T lymphocytes
(autocrine stimulation)
= proliferation
= memory T cells
= clonal effector T cells
How is T helper cell polarisation influenced by Signal 3?
Presence of polarising cytokines (signal 3) during T cell activation
= determines T helper subset differentiation
PRR binding by pathogen antigens
= stimulates secretion of particular cytokines
= these bind to receptors in CD4+ T cells and influence TH differentiation
(under control of a transcription master regulator)
= each subset of TH cells has its own functional properties and produces characteristic cytokines
What are the T helper subsets?
Different types of pathogens stimulate different TH subsets
TH1 subset
= important in cell-mediated
TH2 subset
= important in humoral immunity
= they cross regulate each other biasing the immune response in a particular direction
= subset cross-regulation
Give a summary of the properties of the major T helper subsets
What are memory T cells?
= arise early during a primary immune response
= require T-cell help to persist
= can be CD4+ OR CD8+ phenotype
2 main subsets of memory T cells
- Central memory T cells (TCM)
= found in secondary lymphoid tissues
= respond to reinfection by differentiating into TH subsets under influence of cytokines - Effector memory T cells (TEM)
= found in the periphery
What are the 2 opportunities for B cells?
Once they are within follicles, mature B cells can
= interact with antigen and become activated
OR
= in absence of stimulation, recirculate through blood and lymphatics back to the follicles
(can recur many times)
How does B-cell activation and differentiation occur?
= clonal selection hypothesis:
= each B cells bears a single type of Ig receptor
= on stimulation, each cell will create a clone of cells bearing the same Ag (antigen) receptor as the original
What are the modes of B-cell activation?
Most B cell antigens are T-cell dependent
= need to be presented to TH cells
= so that appropriates help can be delivered via cytokine signalling
Some antigens are T-cell independent
= do not require T cell help if they can stimulate PRRs on B cells
Other antigens may fix complement fragment C3d
= and bind complement receptors on B cells
What are the T-Dependent B-Cell Responses?
B cells bind Ag via BCR:
= this induces initial activation and proliferation events
(proliferation induces formation of germinal centres in lymph nodes / spleen)
= some Ag is internalised and processed
(presented on cell surface in MHC class II molecules)
= interaction with helper T cells provides conditions for differentiation and memory cell production
What happens in antigen presentation to B-cells?
B cells encounter Ag in lymph nodes and spleen
= small soluble Ag acquired from lymphatic circulation by follicular B cells
= larger Ag captured by subcapsular sinus macrophages and handed off to B cells in the follicles
= follicular dendritic cells (FDCs) serve as Ag concentration site for future selection and differentiation
What is B-Cell receptor clustering?
When BCR recognises its specific antigen
= receptors of B-cell membrane briefly spread over the antigen surface = the contract
= resulting in B-cell receptor clustering
= clustering results in internalisation of the receptor-antigen complex followed by antigen presentation by the B cell to a T cell
= T cell / B cell interaction occurs primarily at border between the T and B cell zones of the lymph nodes
What is plasma cell differentiation?
T cells interact with their cognate B cells
= by binding to the processed antigen with their TCR
= as well as by interactions between T cell CD28 with B cell CD80/86
= and between T cell CD40L and B cell CD40
These interactions
= facilitate directional secretion of T-cell cytokines that are necessary for full B-cell activation
Following stimulation of primary B cells at the T-cell/B-cell border within lymph node
= some B cells differentiate quickly into plasma cells that form primary foci + secrete initial wave of IgM antibodies
Other B cells from antigen-stimulated clones
= migrate to the primary follicles and form germinal centres
What is the Germinal Centre (GC) Reaction (as a part of T dependent B cell responses)?
GCs form 4-7 days after initiation of T dependent B cell activation
= a few B cells within extrafollicular foci migrate back to the follicle
= proliferate rapidly
= site of somatic hypermutation (SHM)
= previously thought to be site of class switch recombination (CSR)
What is class switch recombination (as a part of T dependent B cell responses)?
B cells activated by helper T signals
= e.g. CD40L, cytokines
= undergo switching to different Ig isotypes
(which mediate distinct effector functions)
AID (activation-induced cytidine deaminase) initiates DSBs in heavy chain genes
= by deaminating cytidine residues within designated switch regions upstream of the donor and acceptor switch sites
= DSBs are formed
= e.g. change from a Cμ to a Cγ1
What is Somatic Hypermutation (as a part of T dependent B cell responses)?
Within GCs
= B-cell differentiation continues
= with generation of somatically hypermutated receptors
(subject to antigen selection)
= leads to generation of high-affinity antibodies
= somatic hypermutation (SHM) affects certain sequences called mutational hot spots
(in the variable region genes of antibody molecules)
= SHM also mediated bu activation-induced cytidine deaminase (AID) followed by DNA repair
What are Memory B-cells
= produced during a primary response from naive B-cells that do not differentiate into plasma cells
= recirculating B memory cells must be reactivated by antigen
= in order to yield a higher, faster and stronger response than the primary response
What are long-lived plasma cells?
= reside in bone marrow / other locations
= continually secrete antibodies and ensure that antibodies to commonly encountered antigens constantly circulate within blood
What are some T-independent B-cell responses?
TI-1 antigens
= interact with B cells via both the bCR and innate immune response
TI-2 antigens
- highly polymerised antigens that do not have an intrinsic mitogenic activity
Both types
= enhanced by interactions with other cells types
(e.g. T cells, macrophages, monocytes, ?neutrophils)
T-independent responses also generated by B-1 and MZ B cells
= give rise to relatively low-affinity, primarily IgM antibodies (natural antibodies)
What is negative regulation of B-cell responses?
Shutting down BCR signalling may be necessary to stop proliferation when it is no longer required
= B cells can be negatively signalled through the CD22 receptor
(contains an immunoreceptor tyrosine-based inhibitory motif - ITIM)
= FcγRIIb is a receptor that recognises the presence of IgG-containing immune complexes in the blood
= B-10 B cells are subpopulation that release IL-10 upon antigenic stimulation
(cytokine that reduces inflammation during an ongoing immune response)
