L8 - Lymphoid Organs & Lymphocyte Trafficking

Immunology                                                   Key Terms Haemopoiesis ± Production Production of haematopoietic stem cells (precursors of immune cells) Chemokines ±Cytokines ±Cytokines that are involved in t he regulation of mobility. mobility. Germinal Centre ± A transient structure of intense B-cell proliferation Primary Lymphoid Tissues 

W  here lymphocytes are developed  here

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Production, maturation, selection

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aka central lymphoid tissues

Bone Marrow: W  here most B-cells are developed  here The main site is haemopoiesis haemopoiesis in an adult is the bone marrow (in an embryo it is the foetal liv er) Bone marrow is found in the ce ntral medullary cavity of bone The majority of bone marrow is found in our long bones, bones, notably the femur  Precursors are packed in the extracellular spaces (cavities) between sinuses There are other cells here that interact and µhelp¶ the precursors A good area to produce these cells, well protected as deep within bone Thymus: W  here most T-cells are made here Found between lungs, above heart  A bi-lobed organ Each lobe of the thymus is made up of lobules 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, o hormones = q 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 throughout life

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T-cell generation does still continue as an adult 

Cortex may disappear entirely, medulla medulla remains Cortical atrophy atrophy (wasting) is related to the production production of corticosteroid  There is a big o in corticosteroids during pregnancy and stress

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Immunology                                                  

Cortex (outer) 

Tightly packed with cells

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Immature, proliferating proliferating thymic lymphocytes (thymocytes, T-ce lls)

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Site of positive selection

Medulla (inner) 

Loosely packed with cells

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More mature thymocytes

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Site of negative selection

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Site of a lot of cell death

Three types of thymic epithelial cells (TECs) are involved in T-cell development  

Epithelial nurse cells

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Cortical 

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Medullary 

Hassall¶s corpuscle is found in the medulla and might be involved in removing dead cells High endothelial endothelial venules (HEVs) are involved in T -cell exit in the thymus 

Found at the corticomedullary junction

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Immunology                                                   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 

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The interact via cell adhesion molecules They provide soluble factors (most important is interleukin-7)

They still need extra proces sing however, which takes place in the spleen and lymph lymph nodes This processing is to develop a more effective Ig with high affinity for Ag B-cells will migrate migrate as they mature« Earliest Earliest stem cells are found in the sub-endosteum (near the inner bone surface) More mature c ells will remain in contact with stromal cells and move p centre of cavity  T-cell precursors that leave the bone marrow are very immature They then travel to the thymus W  hen they leave the thymus they are completely developed  hen Secondary Lymphoid Tissues 

W  here adaptive immune responses are initiated, and lymphocytes are maintained  here

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aka peripheral lymphoid tissues

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Lymph nodes

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Spleen

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Mucosa-associated lymphoid tissue (MALT) o

Peyer¶s patches

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Tonsils

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Appendix 

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Bronchiole-associated Bronchiole-associated lymphoid tissue (BALT)

Once B-/T-cells have developed, they enter the bloodstream bloodstream and migrate to the peripheral 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 Lymphocytes will recirculate between the blood and the peripheral lymphoid lymphoid organs until they encounter a specific antigen

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Immunology                                                   1. Naïve T-cells T-cells are recirculated between bloodstream / lymph / second ary lymphoid tissues 

T-cell enters the lymph node across an a n HEV (µcatflap¶) (µcatflap¶) 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

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T-cells will will monitor presented antigens

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If the T-cell does not encounter a specific antigen it will leave the lymph node node o

Leave via the th e efferent efferent lymph

3. If the T-cell encounters a specific antigen, it will proliferate proliferate and differentiate 

Activation of T-cells

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Differentiation peffector cells

Afferent = incoming  Efferent = leaving 

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Immunology                                                  

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 a dhesion molecules The primary molecule on B-/T-cells involved with recognition recognition of a lymph node is L-selectin L-selectin recognised recognised two molecules in particular, particular, found on the s urface of HEVs 

GlyCAM-1 GlyCAM-1 ± has a sulphated-sialyl-Lewis sulphated-sialyl-LewisX group (carbohydrate) on its surface

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CD34 ± also as carbohydrate moieties on its surface

This process is not just recognition, it also slows the cells down ± The circulation circulation of blood / lymph moves the B -/T-cells around at  some speed. They need t o 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. interaction. Chemokines will bind to receptors on the incoming T-ce ll. IfIf the concentrations of chemokines are high enough, LFA-1 (an integrin found on the s urface of the T-cell) will be activated through a conformational change induced induced by t he 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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Immunology                                                   T-cells can only encounter an antigen via APCs (a ntigen presenting cells) 

Antigen on an MHC molecule (on an APC)

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The lymphocytes need to get close to the APCs for an interaction to take place

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Also need to be there long enough for an interaction to take place

Molecules Molecules on the surface of the T-cell  interact with molecules of the surface of  dendritic cells: cells: pLFA-3 CD2 

LFA-1 pICAM-1 LFA-1 pICAM-2  ICAM-3 pDC-SIGN  A lot of these molecules are only expres sed on T-cells or  dendritic cells The interactions hold the cells together close enough and long enough for an interaction to occur. These r eactions are low  affinity in comparison comparison to that of an Ag and a T-cell receptor. If the T-cell encounters its specific antigen there there will be an interaction between the peptide Ag (presente d 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 dendritic cell. This interaction can now last f or many hours . The TCR interaction will will cause T -cell proliferation, daughter cells will also recognise the Ag.

Lymph

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

Cortex (B-cell area)

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Paracortex (T-cell area)

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Medulla

Has an afferent v essel (µin tube¶) and an efferent vessel (µout tube¶) Promote crucial interactions between« 

APCs (dendritic cells) and T-cells

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Activated antigen-specific antigen-specific  T- & B-cells

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Primary lymphoid follicles 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 follicular dendritic cells (FDCs) embedded in a B -cell-rich region FDCs display antigen to B-cells During an infection, 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 the FDCs have a lot of complement receptors FDCs also have receptors t hat 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) B-cells in the germinal centres are µfragile¶ and will die with out help

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Immunology                                                   Helped to survive by T  cells (helper T-cells) that have bee n activated in T-cell T-cell areas H  H  

D40L (ligand) that bind C  D40 or B-cell surface Activated T  cells express high levels of C  H  H 

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This rescues dying B-cells B-cells allowing them to proliferate

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Has to be a T  cell that recognises the same antigen as t he B-cell  B-cell  H  H 

DC they can form If B-cells and T-cells interact with the same antigen on a F  f orm a primary follicle 

10% T-cells

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90% B-cells

The primary follicle differentiates into a germinal centre There is a huge amount of proliferation proliferation of B-cells in the germinal centres (dar k zone) B-cells will eventually differentiate, differentiate, affinity maturation will take place then it will move t hrough the HEV  If B-cells recognise a µself¶ antigen, there is a s election process that willremove them to prevent an an autoimmune response.

High Endothelial Venules ( HEVs): [Page 8] 

Immunology                                                   Found in all secondary secondary lymphoid organs other than the spleen Allow 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 lymphocytes to pass efficiently  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 W  hite pulp contains many white blood cells& lymphoid tissue hite Lymphocytes surround a c entral arteriole forming Periateriolar Lymphoid Sheaths (PALS) T-cells surround the central arteriole Primary lymphoid follicles follicles are attached to the PALS  

Rich in B-cells

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Sometimes contain germinal centres

Marginal Zone surrounds the PALS  Contains B-cells, macrophages and dendritic dendritic cells

Mucosa-Associated Lymphoid Tissue ( MALT):

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Immunology                                                   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 near the surface of the gut wall  Epithelial Epithelial M cells transport antigens into the lymphoid tissue 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 ca n 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 ca n be initiated in case the pathogenic pathogenic material enters the bloodstream. bloodstream. The Peyer¶s patches have HEVs through which lymphocytes can enter the blood 

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Immunology                                                  

Captured antigens are then transferred to lymph nodes. Peyer¶s patches are not lymph nodes, and are unable to mount an i mmune response Lymph nodes are placed in strategic positions; positions; skin, gut etc. Crucial in mounting an immune response Have some c ontrol in determining determining what type of immune response is m ounted  e.g. Peyer¶s patches specialise in turning out T  cells making T  2 responses H  H  H  H  

Also B-cells making IgA (perfect for intestinal invasion)

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

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