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MB4030 > Immunological Memory B and T cells > Flashcards

Immunological Memory B and T cells Flashcards

1
Q

Where are mature naive B cells stored

A

Primary follicles

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2
Q

What drives the diversity of B cell repertoire?

A

Combination of VDJ recombinations coupled with n-nucleotide deletions and insertions

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3
Q

Main fates of Naive B Cells

A
  • become plasmabalsts and SLPCs (producing large amounts of Abs)
  • differentiate into LLPCs
  • become Memory B cells
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4
Q

How is the movement of naive B cells slowed?

A

controlled adhesion cascade

  • migration is controlled by cytokines, chemokines and adhesion molecules
  • has circadian component
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5
Q

Types of B cells

A
  • Naive B cells
  • Plasmablasts
  • SLPCs
  • LLPCs
  • Memory B cells
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6
Q

How does lymph arrive and leave lymphatic vessels

A

Arrives via several afferent vessel

Exits via one efferent vessel

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7
Q

How do naive B cells enter LN?

A

High endothelial venules

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8
Q

Where does homing of immune cells from circulation occur?

A

High endothelial venule sites

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9
Q

What is the dominant cell type in the extrafollicular region

A

mature naive B cells

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10
Q

What is the site of B cell proliferation after antigen recognition

A

germinal centre
(where the process of immunological memory occurs)

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11
Q

Where are B lymphocytes predominantly located in LN

A

cortex
(B cell migration occurs here)

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12
Q

Where are T lymphocytes predominantly located in LN

A

paracortex
medulla

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13
Q

Explain the route of naive B cells in the LN

A
  • arrive in LN
  • move to cortex (may or may not encounter antigen)
  • if their antigen is not encountered -> B cells exit and migrate to other LNs or spleen
  • B cells that don’t encounter antigen -> die by neglect (apoptosis)
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14
Q

B cell tethering

A

L-selection on B cells interact with many HEV sialomucins e.g. CD34

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15
Q

B cell arrest

A

chemokine receptors of the B cell surface (CCR7, CXCR4, CXCR5) trigger the expression of LFA-1 on B cells

*an adhesion molecule

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16
Q

Chemokine ligand/receptors examples

A
  • CCL21 expressed on surface of HEVs (CCR7 receptor)
  • CXCL12 (CXCR4 receptor)
  • CXCL13 (CXCR5 receptor)
  • all secreted by LN stromal cells
  • all help to stick to ligands on cell surface and slow down B cell movement
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17
Q

What immobilises these chemokine ligands

A

heparin sulphate

*allows them to interact with CCR7, CXCR4, CXCR5 on B Cells

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18
Q

Where does LFA-1 bind

A

ICAM-1 & ICAM-2

(on HEV)

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19
Q

At what rate do the B cells crawl

A

4 um/minute looking for an entry port

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20
Q

What helps to maintain B cells in the LN

A

Naive B cells continue to be attracted by chemokine CXCL13/CXCR5

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21
Q

B lymphocyte chemoattractant

A

CXCL13

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22
Q

Where to naive B cells migrate to?

A

B cell follicles in LNs and spleen (cortex & paracortex)

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23
Q

At what rate do B cells migrate through subcapsular region

A

~ 6 um/min

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24
Q

BAFF

A
  • released by follicle stromal cell
  • critical B cell survival factor
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25
Q

Specialised APCs

A
  • follicular dendritic cells (FDCs)
  • tingible body macrophages (TBM)

*capture incoming antigen

26
Q

Follicular DCs

A
  • can capture antigens in a non-phagocytic way
  • supply a continuous supply of antigen during B cell response
  • can migrate to B cell zone of LN and display these unprocessed antigens for weeks to B cells
27
Q

What happens if B cell is triggered by its BCR binding its antigen

A
  • BCR and bound antigen is internalised in clathrin-dependent manner
  • antigen travels via endosomes to lysosomes for enzymatic processing
  • peptides loaded onto MHC II
  • allows for presentation to T cells and B cell stimulation
28
Q

Plasmablasts

A
  • if naive lymphocyte is acitivated by recognising its antigen, subset undergoes clonal expansion, differentiates and migrates to extrafollicular foci within LNs
  • PBs secrete low affinity Abs
  • most immature Ab-producing B cell
  • proliferate more, shorter lived than SLPCs
  • dont produce as much AB as SLPCs
  • undergo class-switching to IgG
  • dont undergo SHM
  • affinity for antigen is 1/100 of that of GC B cells
29
Q

The most immature Ab-producing B cell

A

Plasmablasts

30
Q

Differentiated PBs from SLPCs

A
  • proliferate more than SSPCs
  • shorter lived than SSPCs
  • don’t produce as much Ab as SSPCs
31
Q

Subgroups of plasma cells

A

Plasmablasts
SLPCs

32
Q

SLPCs

*8 points

A
  • after antigen encounter, naive B cells proliferate and differentiate into SLPCs
  • produce large amount of Ag-specific Ab of both unswitched (IgM) and class-switched (IgG)
  • accumulate in medullary cords of LNs and red pulp of spleen
  • lifespan corresponds to course of infection
  • metabotically very active (import glucose and AAs required for max Ab synthesis and glycosylation)
  • response is max after 2 weeks from start of infx
  • following infx control-> apoptosis
  • NO ROLE IN LONG TERM MEMORY GENERATION
33
Q

LLPCs

* 7 points

A
  • produced in GCs with memory B cells
  • SLPCs that migrate further into follicile (enter GC response)
  • produce Ab for months/yrs
  • relocate mainly in BM and GALT (dont stay in LNs)
  • SMH and affinity maturation of Abs take place in GCs
  • GC B cells express AID enzyme
  • High mutation rate in B cells -> can lead to genome damage -> GC B cell lymphoma

AID: activation induced deamidase

34
Q

LZ vs DZ

A

LZ: proximal to LN capsule
DZ: proximal to T cell zone

  • B cells enter DZ first and begin to proliferate
  • These B cells contain Bcl6
35
Q

Bcl6

A
  • prevents premature activation and differentiation of GC B cells
  • environment for SHM and CS

*keeps B cells alive in GC

36
Q

CXCR4

A

essential for positioning GC B cells to the DZ

37
Q

What chemokine is produced by DZ

A

CXCL12/SDF-1

38
Q

Function of DZ

A

sites of B cell clonal expansion and SMH

39
Q

Function of LZ

A

-Site of selection by Ag binding B cells

40
Q

How do B cells migrate into LZ

A
  • CXCR4/CCR7 downreg
  • directs B cells to border of T cell zone
  • here they select cells with high affinity for receptor
41
Q

Cell types in LZ

A

FDCs
GC B cells
Naive B cells - TBMs

TBMs: tingible-body macrophages (intact antigen on their surface)

42
Q

Cell types in DZ

A
  • GC B cells
43
Q

How do B cells efficiently internalise antigen from surface of FDCs?

A

require a BCR that has a good affinity for its antigen
- allows string pulling force
- Ag internalised, processed and presented bound to MHC II to Tfh cells

44
Q

Tfh cells

A
  • Tfh stimulate B cells with high numbers of high affinity BCR & MHCII bound peptide receptors
  • express CD4+, Bcl-6+, CXCR5+, PD-1+
  • battle for antigen (high affinity BCRs bind more and rescue them from apoptosis)
  • secrete IL-4, IL-21, IFNy for survival
45
Q

What happens to B cells that dont receive sufficient signals from Tfh cells?

A
  • Fas mediated apoptosis (FasL on Tfh)
  • this selects for B cells with high affinity for antigen -> force them to compete with Tfh
  • these high affinity B cells become LLPCs or memory B cells
46
Q

Memory B cells

A
  • form lifelong immunity
    e.g. MBC to smallpox detected over 50 yrs after vaccination
  • GC derived
  • class switched, hypermutated
  • quiescent cells
  • require restimulaion to contribute to memory response
  • located in LNs and spleen
  • proliferate faster than naive B cells to form plasmablasts/LLPCs
  • can re-enter GCs and undergo SHM/proliferation -> produce more MBCs
47
Q

reactivated MBCs

A

-re-exposure to Ag leads to rapid re-activation of MBCs in spleen & liver
- produce to Ab secreting SLPCs
- give rise to LLPCs

48
Q

Affinity maturation of Abs

A
  • SHM
  • selective survival for B cells producing Abs with highest affinities
  • takes place in GCs in LNs and spleen
  • conc. of Ag decreases with time, B cells with higher affinity for Ag receive survial signals from DCs and Tfh cells
  • also turn on anti-apoptotic pathways
49
Q

Function of FDCs

A

can sequester B cell antigen and continually stimulate B cell
(crucial for LLPCs and MBCs survival)

50
Q

What initates SHM

A

AID
(activation-induced cytokine deaminase)

  • preferentially targets transcriptionally active regions of Immunoglobulin HC locus
51
Q

Function of SHM

A
  1. Brings about point mutations in V gene
  2. Affinity maturation of Ab (generates Abs w/ both higher and lower affinities)
    - mutation can change NT sequence of B cell by 5%
52
Q

Example of high SHM levels

A

Seen in chronic viral infxs
15-30& NT substitutions seen in CDR regions producing anti HIV Abs

53
Q

Earliest B cell/Ab response

A

Plasmablasts

54
Q

Plasmablasts features

A
  • short lived
  • low affinity Abs
55
Q

SLPCs features

A
  • live for duration of infx
  • make large amount of Ab (IgG and IgM)
56
Q

LLPCs

A
  • live for yrs
  • reside in BM and GALT
  • produce high-affinity Abs of all subclasses
  • have undergone SHM in GCs
57
Q

MBCs

A
  • located in GCs of LNs and spleen
  • undergo affinity maturation of Ab by multiple rounds of SHM
  • respond to subsequent w/ same pathogen by giving rise to SSPCs, LLPCs, more MBCs
58
Q

CD4+ Th cells

A

-produce cytokines that help phagocytes, APCs, B cells, CTLs, NKs

59
Q

CTLs

A
  • large TCR repertoire to recognise all peptides/Ags from pathogens
  • recognise peptides bound to mHC on surface of virus-infected cells and cancer cells
  • kill these cells by apoptosis
60
Q

NKs

A
  • detect and kill cells with no self MHC molecules on their surface
61
Q

Tregs

A
  • control and regulate immune response by suppressing/downregulating immune response once infx is controlled
62
Q

Classes of Th cells

A

Th1: IFNy
Th2: IL4,5,13
Th3: IL17,22
Tfh: IL21, IFNy, IL4

MB4030 (11 decks)

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