T/B cell activation, differentiation and memory

Question 1

How is the adaptive immune response initiated?

Answer 1

= 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

Question 2

What are the stages of T cell activation and differentiation? (summary)

Answer 2

Antigen recognition

Activation

Clonal Expansion

Differentiation

Effector functions

Question 3

What is T cell recirculation?

Answer 3

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

Question 4

How are T cells activated?

Answer 4

= 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

Question 5

What are some co-stimulatory receptors?

Answer 5

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)

Question 6

What does absence of co-stimulation lead to?

Answer 6

= 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

Question 7

What are some examples of Antigen-Presenting Cells?

Answer 7

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

Question 8

What are Superantigens?

Answer 8

= 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

Question 9

What occurs during T cell differentiation?

Answer 9

= 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

Question 10

How is T helper cell polarisation influenced by Signal 3?

Answer 10

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

Question 11

What are the T helper subsets?

Answer 11

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

Question 12

Give a summary of the properties of the major T helper subsets

Answer 12

Question 13

What are memory T cells?

Answer 13

= 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

1. Central memory T cells (TCM)
   = found in secondary lymphoid tissues
   = respond to reinfection by differentiating into TH subsets under influence of cytokines
2. Effector memory T cells (TEM)
   = found in the periphery

Question 14

What are the 2 opportunities for B cells?

Answer 14

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)

Question 15

How does B-cell activation and differentiation occur?

Answer 15

= 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

Question 16

What are the modes of B-cell activation?

Answer 16

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

Question 17

What are the T-Dependent B-Cell Responses?

Answer 17

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

Question 18

What happens in antigen presentation to B-cells?

Answer 18

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

Question 19

What is B-Cell receptor clustering?

Answer 19

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

Question 20

What is plasma cell differentiation?

Answer 20

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

Question 21

What is the Germinal Centre (GC) Reaction (as a part of T dependent B cell responses)?

Answer 21

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)

Question 22

What is class switch recombination (as a part of T dependent B cell responses)?

Answer 22

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

Question 23

What is Somatic Hypermutation (as a part of T dependent B cell responses)?

Answer 23

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

Question 24

What are Memory B-cells

Answer 24

= 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

Question 25

What are long-lived plasma cells?

Answer 25

= reside in bone marrow / other locations

= continually secrete antibodies and ensure that antibodies to commonly encountered antigens constantly circulate within blood

Question 26

What are some T-independent B-cell responses?

Answer 26

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)

Question 27

What is negative regulation of B-cell responses?

Answer 27

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)