L17: T and B cell cooperation

Question 1

BCR signalling

Answer 1

BCR consists of membrane-bound Ig (H&L chains) signalling molecules (Ig-alpha and beta). Full B cell activation requires signalling through BCR + 2nd signal delivered by T helper cells or TI antigens. Activation via BCR: cell proliferation, functional responses.

Question 2

BCR Co-receptor

Answer 2

1. BCR co-receptor sensitises BCR responses
2. Antigens covalently attached to C3d bind CD21 -allows clustering
3. CD19 phosphorylation allows binding and activation of src kinase members - amplification of response

Question 3

Thymus-dependent and -independent antigens

Answer 3

B cell activation requires 2 signals:
1. TD antigens: T helper cells provide 2nd signal
2. TI antigens: antigen can provide 2nd signal directly
TI and TD antigens: both trigger B cell proliferation and IgM production
TD antigens efficiently trigger: isotype switching, somatic hypermutation and affinity maturation, memory B cell formation

Question 4

Signals provided by TI antigens

Answer 4

1. TI-1 antigen: intrinsic ability to stimulate B cell proliferation
2. TI-2 antigen: cross-link BCR

Question 5

Signals provided by TD antigens

Answer 5

Key Th signals:

1. CD40L (CD154): TNF family member induced on CD4+ T cells after B cell presents Ag; drives B cell into cell cycle; required for isotype switching
2. Cytokines: IL-4 (Th2 cell) drives B cell proliferation in synergy with CD40L, IL-5/6 also promotes B cell activation, various cytokines promote class switching

Question 6

T/B cell co-operation

Answer 6

Link recognition: B cells take up antigen and present it to T cells. Helper T cell adheres to B cell and begins to synthesise IL-4 and CD40L, reorients cytoskeleton and secretory apparatus toward the B cell. IL-4 is released into confined space between B and T cell.

Question 7

Germinal Centre Formation 1:

Answer 7

T and B cells occupy distinc zones of lymphoid tissue, enter through HEV. APC that capture Ag migrate from tissue to T cell zones of LN. B cells enter HEV pass through T cell zone into B cell zone. B cells binding Ag trapped in T cell zone. T/B cell expansion = primary focus formation. B cells migrate to medullary cords or migrate with T cells to B cell area (primary/lymphoid follicles) and form germinal centres

Question 8

B cell expansion in GC

Answer 8

1. Centroblasts = rapidly dividing cells with expanded cytoplasm in GC dark zone
2. Centrocytes = cells that stop dividing in GC light zone

Question 9

Follicular Dendritic Cells (FDC)

Answer 9

In lymphoid follicles, retain Ag on their cell surface for long periods and provide survival signals to B cells in the mantle zone.

Question 10

Evolution of affinity/affinity maturation and GC formation

Answer 10

Within GC, B cells undergo affinity maturation controlled by CD40L/CD40. Somatic hypermutation occurs and B cells with highest Ag affinity are selected. This happens in centroblasts so that centrocytes have modified Ag affinity. Centrocytes with high affinity get survival signals from FDC+Ag. T/B cell cooperation acts as final check point to ensure no-self reactivity. B cells then become plasma or memory cells.

Question 11

Follicular helper T cells (TfH cells)

Answer 11

T cells that provide help to B cells during responses to TD antigens. Express high CXCR5 chemokine receptor and low CCR7, enabling homing to lymphoid follicles within secondary lymphoid organs. Express Bcl-6 (transcription factor) which promotes TfH gene expression.