L18: Immunological memory in T and B cells

Question 1

Immunological memory (4)

Answer 1

1. Primary Response: first encounter of antigen
2. Recall antigen: antigen previously encountered by host
3. Memory B and T cells: enable quicker, stronger, longer-lasting response to recall antigen due to functional changes in memory cells, basis for vaccine technology
4. Memory B and T cell survival: long-lived cells, long lifespan of memory lymphocytes due to low antigen concentrations persist or endogenous factors support survival

Question 2

Phases of immune response (3)

Answer 2

1. Innate immune response (0-4 hrs): anti-microbial peptides and enzymes; mechanical barriers; competition with normal flora; phagocytic cells; alternate and mannose-binding lectin pathways for complement activation
   Early induced response (4-96hrs): release of inflammatory mediators by phagocytes, NK cell activation, CD5 B cells recognise TI-2 antigens and produce IgM
   Late adaptive response (>96hrs): antigen transport to lymph nodes, T/B cell recognition, clonal expansion of lymphocytes

Question 3

Upon reinfection (2)

Answer 3

1. Protective immunity: recognition by pre-formed antibody and effector T cells. Infectious agent removed
2. Immunological memory: recognition by memory B and T cells, rapid expansion and activation of effector cells. Infectious agent removed.

Question 4

B cell memory - function changes (5)

Answer 4

1. Primary response: low affinity IgM
2. Secondary response: IgG, IgA and IgE (higher affinity for antigen)
3. Memory B cells undergone class switching/affinity maturation: Naive = IgM/IgD positive, memory IgG/IgA positive
4. In secondary and subsequent responses, antibody levels produced rise
5. Memory B cells divide more rapidly and have lower threshold for activation: enhanced affinity for antigen, enhanced expression of MHC 2, memory B cells take up/present Ag to Th cells at low Ag levels

Question 5

B cell memory - endogenous survival factors (2)

Answer 5

1. Compared to naive B cells, memory B cells express high levels of nerve growth factor (TNF member) & NGF receptors (TNF-R member)
2. NGF = survival signal for memory B cells (autocrine factor), blocking NGF downregulates bcl-2 expression (anti-apoptotic) and secondary antibody responses

Question 6

T cell memory - functional changes (4)

Answer 6

1. TCR does not undergo class switching or somatic hypermutation
2. Major marker differentiating memory T cells from naive T cells: CD45, CD45RO on memory T cells, CD45RA on naive T cells; different CD45 isoforms associated with differential TCR signalling
3. Memory T cells can be sorted into distinct subpopulations (Tem and Tcm)
4. Effector function (Tem) and B cell help (Tcm)

Question 7

Tem

Answer 7

Effector memory T cells (CD45RO+, CCR7-, CD62Llow); home to peripheral tissues/away from lymph nodes, rapid response to re-challenge with infectious agent

Question 8

Tcm

Answer 8

Central memory T cells (CD45RO+. CCR7+, CD62Lhigh); home to LN, can initiate further T/B cell cooperation

Question 9

T cell memory - endogenous survival factors (2)

Answer 9

1. IL-15/IL-7: survival and proliferation signal for memory CD8+ and CD4 T cells
2. Memory CD4+ T cells express some TLRs: infectious permit CD4+ T cell survival

Question 10

Naive vs Memory T cells

Answer 10

1. Naive: CD45RA+, CD26L high, CCR7+, CD44low (adhesion molecule)
2. Central: CD45RO+, CD26Lhigh, CCR7+, CD44high
3. Effector: CD45RO+, CD26Llow, CCR7-, CD44high

Question 11

CD45 (leukocyte common antigen)

Answer 11

1. Protein tyrosine phosphatase required for TCR and BCR signalling
2. Dephosphorylates src family members to activate them
3. Binds CD45L that is expressed on APC
4. Has 3 variable exons which can be alternatively spliced (A, B, C)
5. Two isoforms differentiate naive from memory cells (CD45RA and CD45RO)

Question 12

CD45RA

Answer 12

Larger form expressed on Naive T cells, Exon A is present in extracellular domain, doesn’t pre-associate with the T cell receptor complex

Question 13

CD45RO

Answer 13

Shorter form expressed on memory T cells, no exon A/B/C, associates with T cell receptor complex and CD4/CD8, rapid signalling through TCR upon activation

Question 14

CD62L (L-selectin)

Answer 14

1. Selectins recognise specific carbohydrate domains
2. Required for lymphocyte homing to lymph nodes.
3. Binds CD34 expressed on HEV of LN and MadCAM-1 expressed on HEV of MALT
4. Downregulation on some memory cells (Tem) targets them away from secondary lymphoid tissues to site of challenge.

Question 15

CCR7

Answer 15

1. Chemokine receptor that binds to secondary lymphoid tissue chemokine (SLC)
2. As lymphocytes migrate through HEV they bind to adhesion molecules on endothelial cells through CD62L
3. Allows for engagement of CCR7 on the T cell with SLC on the endothelial cell: firm adhesion and migration into lymph nodes
4. Downregulation on some memory T cells (Tem) targets these cells to peripheral tissue where they carry out effector functions

Question 16

Central memory T cells

Answer 16

1. Markers: CD45RO+ CD62Lhigh, CCR7+
2. Targeted to lymph node
3. Readily activated than naive T cells: CD45RO association with TCR - low activation threshold; express CD40L more rapidly and at higher levels than naive T cells; rapid help to B cells after secondary stimulation
4. Have weak effector function and are inefficient producers of: IFN-gamma (Th1); IL4/5; and perforin (CTL)

Question 17

Effector memory T cells

Answer 17

1. Markers: CD45RO+ CD62Llow, CCR7-
2. Targeted to peripheral tissue
3. Home to inflamed tissues because express high levels of integrins and receptors for inflammatory chemokines CCR1, CCR3, CCR5
4. Have strong effector function and are efficient producers of: IFN-gamma (Th1); IL4/5; and perforin (CTL)

Question 18

Tissue-resident memory (TRM)

Answer 18

1. Phenotype: CD62L-, CCR7- CD103+, CD69+
2. Localisation: epithelial layers in non-lymphoid tissues (gut, skin, lung, glands), brain
3. Functional properties: decrease proliferative potential and IL-2 (no recirculation, increase effector function