Immunology Lymphoid Organs & Lymphocyte Trafficking

Key Terms

Haemopoiesis – Production of haematopoietic stem cells (precursors of immune cells)

Chemokines – Cytokines that are involved in the regulation of mobility.
Germinal Centre – A transient structure of intense B-cell proliferation

Primary Lymphoid Tissues

 Where lymphocytes are developed
 Production, maturation, selection
 aka central lymphoid tissues

Bone Marrow:
Where most B-cells are developed

The main site is haemopoiesis in an adult is the bone marrow (in an embryo it is the foetal liver)
Bone marrow is found in the central medullary cavity of bone
The majority of bone marrow is found in our long bones, notably the femur
Precursors are packed in the extracellular spaces (cavities) between sinuses
There are other cells here that interact and ‘help’ the precursors
A good area to produce these cells, well protected as deep within bone

Thymus:
Where most T-cells are made
Found between lungs, above heart
A bi-lobed organ
Each lobe of the thymus is made up of lobules
Lobules are separated by connective tissue (trabeculae)
Each lobule is made up of an outer cortex and an inner medulla
Sensitive to hormone levels,  hormones =  thymus size
Thymus is largest early in life, this is when most T-cells are produced and stockpiled
 Size begins to decrease in puberty and throughout life
 T-cell generation does still continue as an adult
Cortex may disappear entirely, medulla remains
Cortical atrophy (wasting) is related to the production of corticosteroid
There is a big  in corticosteroids during pregnancy and stress

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Cortex (outer)
 Tightly packed with cells
 Immature, proliferating thymic lymphocytes (thymocytes, T-cells)
 Site of positive selection

Medulla (inner)
 Loosely packed with cells
 More mature thymocytes
 Site of negative selection
 Site of a lot of cell death
Three types of thymic epithelial cells (TECs) are involved in T-cell development
 Epithelial nurse cells
 Cortical
 Medullary

Hassall’s corpuscle is found in the medulla and might be involved in removing dead cells

High endothelial venules (HEVs) are involved in T-cell exit in the thymus
 Found at the corticomedullary junction

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B-cells & T-cells

Both start off in the bone marrow

B-cells mature a lot in the bone marrow and have surface Igs when they leave
B-cell development in the bone marrow is dependent on non-lymphoid stromal cells
 The interact via cell adhesion molecules
 They provide soluble factors (most important is interleukin-7)
They still need extra processing however, which takes place in the spleen and lymph nodes
This processing is to develop a more effective Ig with high affinity for Ag

B-cells will migrate as they mature…

Earliest stem cells are found in the sub-endosteum (near the inner bone surface)
More mature cells will remain in contact with stromal cells and move  centre of cavity

T-cell precursors that leave the bone marrow are very immature
They then travel to the thymus
When they leave the thymus they are completely developed

Secondary Lymphoid Tissues

 Where adaptive immune responses are initiated, and lymphocytes are maintained
 aka peripheral lymphoid tissues
 Lymph nodes
 Spleen
 Mucosa-associated lymphoid tissue (MALT)
o Peyer’s patches
o Tonsils
o Appendix
o Bronchiole-associated lymphoid tissue (BALT)

Once B-/T-cells have developed, they enter the bloodstream and migrate to the peripheral
lymphoid organs, whose main role is to expose lymphocytes to antigens
These tissues are the sites of lymphocyte activation by antigen
The tissues provide signals to sustain re-circulating lymphocytes
Lymphocytes will recirculate between the blood and the peripheral lymphoid organs until they
encounter a specific antigen

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1. Naïve T-cells are recirculated between bloodstream / lymph / secondary lymphoid tissues
 T-cell enters the lymph node across an HEV (‘catflap’) in the cortex
2. A naïve T-cell encounters an antigen that is presented by a macrophage or dendritic cell
 This occurs in the medulla
 T-cells will monitor presented antigens
 If the T-cell does not encounter a specific antigen it will leave the lymph node
o Leave via the efferent lymph
3. If the T-cell encounters a specific antigen, it will proliferate and differentiate
 Activation of T-cells
 Differentiation  effector cells

Afferent = incoming
Efferent = leaving

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T-cells and B-cells need to be encouraged to enter lymphoid tissue

Needs to recognise the epithelial cells of the HEV
This is mediated by adhesion molecules

The primary molecule on B-/T-cells involved with recognition of a lymph node is L-selectin
L-selectin recognised two molecules in particular, found on the surface of HEVs
 GlyCAM-1 – has a sulphated-sialyl-LewisX group (carbohydrate) on its surface
 CD34 – also as carbohydrate moieties on its surface

This process is not just recognition, it also slows the cells

down – The circulation of blood / lymph moves the B-/T-
cells around at some speed. They need to be slowed if they
are going to enter a lymph node. The binding of
L-selectin to CD34 or GlyCAM-1 starts the rolling
interaction.

Chemokines will bind to receptors on the incoming T-cell. If

the concentrations of chemokines are high enough,
LFA-1 (an integrin found on the surface of the T-cell) will be
activated through a conformational change induced by the
chemokine receptor binding to it. LFA-1 will now bind to
ICAM-1, a cell surface receptor on the HEV. There will now
be tight binding between the T-cell and the HEV.
Diapedesis then takes place, the lymphocyte moves from
the blood to the lymph node through gaps between cells.

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T-cells can only encounter an antigen via APCs (antigen presenting cells)
 Antigen on an MHC molecule (on an APC)
 The lymphocytes need to get close to the APCs for an interaction to take place
 Also need to be there long enough for an interaction to take place

Molecules on the surface of the T-cell interact with molecules of the surface of dendritic
cells:
CD2  LFA-3
LFA-1  ICAM-1
LFA-1  ICAM-2
ICAM-3  DC-SIGN

A lot of these molecules are only expressed on T-cells or

dendritic cells

The interactions hold the cells together close enough and

long enough for an interaction to occur. These reactions
are low affinity in comparison to that of an Ag and a T-
cell receptor.

If the T-cell encounters its specific antigen there will be an interaction between the peptide Ag
(presented by MHC class II) and its Ag-receptor. Binding of the TCR will activate intracellular
signalling, which will change the LFA-1 conformation, resulting in it binding tightly to ICAM-1. The
T-cell is now strongly bound to the dendritic cell. This interaction can now last for many hours. The
TCR interaction will cause T-cell proliferation, daughter cells will also recognise the Ag.

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Lymph Nodes:
Encapsulated bean-shaped structure
Clustered at junctions of lymphatic vessels
Found in the neck, armpit, groin, gut etc.
Filter and trap antigens from lymph

Lymph nodes consist of:

 Cortex (B-cell area)
 Paracortex (T-cell area)
 Medulla

Has an afferent vessel (‘in tube’) and an efferent vessel (‘out tube’)

Promote crucial interactions between…

 APCs (dendritic cells) and T-cells
 Activated antigen-specific T- & B-cells

Primary lymphoid follicles can differentiate into germinal centres (important in B-cell activation)

Lymphoid Follicles:

All secondary lymphoid organs have them

Start off as a network of follicular dendritic cells (FDCs) embedded in a B-cell-rich region
FDCs display antigen to B-cells

During an infection, complement binds to pathogen, which is coated in Ag

This is then delivered to the secondary lymphoid organs
FDCs have a lot of complement receptors, so the FDCs will get covered in Ag
The dendrites on the FDCs have a lot of complement receptors
FDCs also have receptors that bind the constant region of antibodies
FDCs can hold antigens for months

FDCs display antigens in a way that can cross-link B-cell receptors

B-cells with receptors cross-linked by Ag coating the FDCs will proliferate to form germinal
centres, and will later differentiate to plasma cells.
FDCs are not DCs (dendritic cells)

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B-cells in the germinal centres are ‘fragile’ and will die without help
Helped to survive by TH cells (helper T-cells) that have been activated in T-cell areas
 Activated TH cells express high levels of CD40L (ligand) that bind CD40 or B-cell surface
 This rescues dying B-cells allowing them to proliferate
 Has to be a TH cell that recognises the same antigen as the B-cell
If B-cells and T-cells interact with the same antigen on a FDC they can form a primary follicle
 10% T-cells
 90% B-cells
The primary follicle differentiates into a germinal centre

There is a huge amount of proliferation of B-cells in the germinal centres (dark zone)

B-cells will eventually differentiate, affinity maturation will take place then it will move through the
HEV

If B-cells recognise a ‘self’ antigen, there is a selection process that will remove them to prevent
an autoimmune response.

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High Endothelial Venules (HEVs):

Found in all secondary lymphoid organs other than the spleen
Allow the passage of T-/B-cells between blood and secondary lymphoid organs
There is enough space between the cells in HEVs to allow lymphocytes to pass efficiently

The Spleen:

A fist-sized organ found behind the stomach

Collects antigens from the blood
Disposes of ageing red blood cells
Trabecular artery separates compartments

Trabecular artery

Red pulp contains many red blood cells

Makes up the majority of the spleen
Site of RBC disposal
Venous sinuses contain resident macrophages, erythrocytes, platelets and some lymphocytes

White pulp contains many white blood cells & lymphoid tissue
Lymphocytes surround a central arteriole forming Periateriolar Lymphoid Sheaths (PALS)
T-cells surround the central arteriole
Primary lymphoid follicles are attached to the PALS
 Rich in B-cells
 Sometimes contain germinal centres

Marginal Zone surrounds the PALS

Contains B-cells, macrophages and dendritic cells

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Mucosa-Associated Lymphoid Tissue (MALT):

Protects mucus membranes lining the digestive, respiratory and urogenital systems
These regions are more exposed to pathogens

BALT = Bronchiole Associated

GALT = Gut Associated

Tonsils + appendix

Peyer’s patches are found within the intestinal lining

They monitor what is happening in the gut
Found near the surface of the gut wall
Epithelial M cells transport antigens into the lymphoid tissue from
the lumen of the small intestine. Membrane ruffles help to pick
up antigens from the gut on microvilli. Endocytosis brings the
Ags in. The M cells are selective in that they can only bring in
antigens that bind to receptors on their cell surface. The
subtypes of molecules they bring in are those that could be
pathogen related. Pathogens will generally have molecules that
allow them to bind to host cells anyway, this is what allows them to be infectious.

This way an immune response can be initiated in case the pathogenic material enters the
bloodstream.

The Peyer’s patches have HEVs through which lymphocytes can enter the blood

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Captured antigens are then transferred to lymph nodes.

Peyer’s patches are not lymph nodes, and are unable to mount an immune response

Lymph nodes are placed in strategic positions; skin, gut etc.

Crucial in mounting an immune response
Have some control in determining what type of immune response is mounted

e.g. Peyer’s patches specialise in turning out TH cells making TH2 responses
 Also B-cells making IgA (perfect for intestinal invasion)

In terms of lymphocyte trafficking, the movement of naïve and activated lymphocytes differs
We want the naïve cells to be circulating and the activated cells to go to infection sites
Surface molecules such as L-selectin (found on naïve T-cells) will direct their movement
The surface molecules will differ on naïve / activated cells

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