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MB4030 > Immunological Memory B and T cells > Flashcards

Immunological Memory B and T cells Flashcards

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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
Specialised APCs
- follicular dendritic cells (FDCs) - tingible body macrophages (TBM) | *capture incoming antigen
26
Follicular DCs
- 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
What happens if B cell is triggered by its BCR binding its antigen
- 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
Plasmablasts
- 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
The most immature Ab-producing B cell
Plasmablasts
30
Differentiated PBs from SLPCs
- proliferate more than SSPCs - shorter lived than SSPCs - don't produce as much Ab as SSPCs
31
Subgroups of plasma cells
Plasmablasts SLPCs
32
SLPCs | *8 points
- 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
LLPCs | * 7 points
- 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 ## Footnote AID: activation induced deamidase
34
LZ vs DZ
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
Bcl6
- prevents premature activation and differentiation of GC B cells - environment for SHM and CS ## Footnote *keeps B cells alive in GC
36
CXCR4
essential for positioning GC B cells to the DZ
37
What chemokine is produced by DZ
CXCL12/SDF-1
38
Function of DZ
sites of B cell clonal expansion and SMH
39
Function of LZ
-Site of selection by Ag binding B cells
40
How do B cells migrate into LZ
- CXCR4/**CCR7** downreg - directs B cells to border of T cell zone - here they select cells with high affinity for receptor
41
Cell types in LZ
FDCs GC B cells Naive B cells - TBMs ## Footnote TBMs: tingible-body macrophages (intact antigen on their surface)
42
Cell types in DZ
- GC B cells
43
How do B cells efficiently internalise antigen from surface of FDCs?
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
Tfh cells
- 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
What happens to B cells that dont receive sufficient signals from Tfh cells?
- 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
Memory B cells
- 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
reactivated MBCs
-re-exposure to Ag leads to rapid re-activation of MBCs in spleen & liver - produce to Ab secreting SLPCs - give rise to LLPCs
48
Affinity maturation of Abs
- 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
Function of FDCs
can sequester B cell antigen and continually stimulate B cell (crucial for LLPCs and MBCs survival)
50
What initates SHM
AID (activation-induced cytokine deaminase) - preferentially targets transcriptionally active regions of Immunoglobulin HC locus
51
Function of SHM
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
Example of high SHM levels
Seen in chronic viral infxs 15-30& NT substitutions seen in CDR regions producing anti HIV Abs
53
Earliest B cell/Ab response
Plasmablasts
54
Plasmablasts features
- short lived - low affinity Abs
55
SLPCs features
- live for duration of infx - make large amount of Ab (IgG and IgM)
56
LLPCs
- live for yrs - reside in BM and GALT - produce high-affinity Abs of all subclasses - have undergone SHM in GCs
57
MBCs
- 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
CD4+ Th cells
-produce cytokines that help phagocytes, APCs, B cells, CTLs, NKs
59
CTLs
- 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
NKs
- detect and kill cells with no self MHC molecules on their surface
61
Tregs
- control and regulate immune response by suppressing/downregulating immune response once infx is controlled
62
Classes of Th cells
Th1: IFNy Th2: IL4,5,13 Th3: IL17,22 Tfh: IL21, IFNy, IL4

MB4030 (11 decks)

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