Functional Anatomy of the Adaptive Immune Response

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Functional Anatomy of the Adaptive Immune
Response
Jason Cyster

• Describe the principal functions of spleen, lymph
  nodes, tonsil
• Explain how lymphocytes get from the blood into a
  lymph node
• Describe the mechanism of dendritic cell antigen
  transport
• Understand how B cells encounter antigen
• Describe changes in effector T cells that permit
  migration to sites of inflammation

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Lymphatics
Lymph is filtered by Lymph Nodes before returning
to circulation (liters per day) Lymph contains T
and B cells and dendritic cells
(thin walled)
One-way valves
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Anatomy of a Lymph Node

• Filter antigens from the lymph
• for recognition by T and B cells
• for destruction by macrophages to prevent
  systemic spread

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Spleen - A filter of the blood

• Two main functions of the spleen carried out in
  two major regions
• 1) White-pulp is where immune responses against
  blood-borne antigens occur
• 2) Red-pulp is responsible for monitoring and
  removing old or damaged RBC
• Red-pulp consists of thin walled splenic (or
  venous) sinuses and dense collections of blood
  cells (including numerous macrophages) that form
  red-pulp cords (or cords of Billroth)
• Blood supply branches of central arteries open
  directly into red-pulp cords, adjacent to the
  splenic sinuses (open circulation)
• Released RBC must cross the sinus walls
  interendothelial slits are a major mechanical
  barrier and only the most supple, mechanically
  resilient RBC survive old and damaged cells are
  removed by macrophages

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Follicle (B zone)
Anatomy of the Spleen
Red Pulp cord
Splenic (venous) sinus
White-Pulp cord
PALS or T zone (periarterial lymphoid sheath)
Pulp vein
Capsule
Trabecular vein
Trabecular artery
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SECONDARY LYMPHOID ORGANS
Mucosal lymphoid tissue (e.g. Tonsil, Appendix)
Splenic White-Pulp Cord
Lymph Node
B cell follicle
T cell zone
red-pulp
- filter antigens from body fluids - bring
together antigen presenting cells and
lymphocytes - help bring together antigen
reactive B and T cells
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Lymphocytes traverse HEVs to enter lymph nodes
and then compartmentalize in B cell follicles and
T cell zones

• Follicle or B zone
• B cells
• FDCs

HEV (High Endothelial Venule)

• T cell zone (paracortex)
• T cells
• DCs

LN section stained with B cell marker L-selectin
ligand
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The cascade (multistep) model of leukocyte
extravasation
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Selectins

• lectins are sugar (carbohydrate)-binding
  proteins selectins are a specialized type of
  lectin that bind appropriately glycosylated
  membrane proteins
• Three types
• L-selectin restricted to lymphocytes
• ligands on lymphoid tissue HEVs
• P-selectin made by platelets and activated
  (inflammed) endothelium
• E-selectin made by activated (inflammed)
  endothelium
• E- and P-selectin ligands expressed on
  neutrophils, monocytes, activated T lymphocytes

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Chemoattractant-Cytokines or Chemokines
gt40, small secreted proteins Four families C,
CC, CXC, CX3C
chemokine
outside
chemokine receptor
cytoplasm
Cells with the appropriate receptor migrate
(chemotax) up chemokine gradient Chemokines also
promote cell adhesion to endothelium Lymphoid
chemokines help direct the homeostatic
trafficking of cells through lymphoid tissues
(e.g. CCR7 / CCL21 CXCR5 / CXCL13) Inflammatory
chemokines induced at sites of inflammation
can be expressed by many cell types help recruit
cells to these sites (e.g. CXCR2 / IL-8
CCR2/MCP1)
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Integrins

• heterodimers of ? and ? polypeptide chains
• can be in inactive (low affinity for ligand) and
  active states
• intracellular signals can cause inside-out
  signaling in the integrin, converting it from an
  inactive to an active state
• chemokine and antigen receptor signaling can
  activate integrins
• bind extracellular matrix proteins (e.g. ????
  binds fibronectin) or transmembrane proteins
  
  (e.g. integrin LFA1 binds ICAM1
  integrin ???? binds VCAM1)

?
?
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Cascade Model of Lymphocyte Recruitment into
Lymph Nodes
HEV
blood flow
STEP 1 Tethering and Rolling L-Selectin-glycosyl
ated HEV ligands
STEP 2 Integrin Triggering Chemokines (e.g.
CCR7- CCL21)
STEP 3 Firm Adherence LFA1/ICAM1
STEP 4 Transmigration
HEV
Lymphoid Tissue
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Multi-step cascade of lymphocyte migration to
site of infection/inflammation same logic,
different area code

• Inhibitor of ?????integrin (tysabri) in
  clinical use for treatment of Multiple Sclerosis

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Schematic view of a lymph node
CXCL13
Follicle
Paracortex
CCL21
Medulla
B zones produce a B cell attracting chemokine T
zone produces T cell and DC attracting chemokines
CXCL13 -gt CXCR5 CCL21 -gt CCR7
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DCs migrate from periphery to lymphoid organ T
zone bearing Ag

• immature sentinel DCs are present in most
  tissues, continually sampling their
  microenvironment for antigen
• by pinocytosis, phagocytosis and engulfment of
  apoptotic cells
• detection of danger signals (e.g. LPS, dsRNA,
  bacterial DNA, necrotic cells, TNF, IL-1) causes
  the cells to mature
• decrease adhesion to local tissue cells (e.g.
  keratinocytes)
• increase expression of receptors (CCR7) for
  chemokines made by lymphatic endothelial cells
  and lymphoid organ T zones
• upregulate MHC and costimulatory molecules
• migrate into lymphoid T zone
• present antigen to T cells

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Immature (sentinel) DCs in tracheal epithelium
longitudinal section
tangential section
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DCs migrate from periphery to lymphoid organ T
zone bearing antigen
Skin draining Lymph Node
Follicle
T zone
DC
LC Langerhans Cell, the immature DC of the skin
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B cell antigen encounter
antigen
lymph fluid
Sinus Macrophage
FDC
hev

• B cells bind intact antigen through their
  surface Ig / B cell receptor (BCR)
• Antigen that enters via blood or lymph reaches
  the follicle and can be captured directly by B
  cells
• Follicular dendritic cells (FDCs tissue
  resident cells related to fibroblasts) can
  display antigen on their surface in an intact
  form for long periods

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Lymph node egress occurs in response to a
circulatory lipid (sphingosine-1-phosphate, S1P)

• Lymphocytes express a receptor (S1PR1) for S1P
• Egress involves migrating to S1P that is high in
  blood/lymph and low in the tissue

MEDULLARY SINUSES
S1P
Diagram courtesy of Ted Yednock
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Lymphocytes express S1PR1 and exit lymphoid
organs in response to S1P
thymus, spleen
lymph node, Peyers patch
S1PR1
S1PR1
S1P lyase
S1P lyase
RBC
S1P
S1P
blood
efferent lymph

• S1PR1 is required for T cell egress from thymus
  and for T and B cell egress from spleen, lymph
  nodes, tonsil
• Activated lymphocytes transiently down-regulate
  S1PR1 and are retained in the responding lymphoid
  tissue until they become effectors
• FTY720 (Fingolimod) inhibits egress and is in
  clinical development as an immunosuppressant (FDA
  approved in 2010 for treatment of multiple
  sclerosis)

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Effector T cell Trafficking

• Activated T cells exit lymphoid tissue -gt
  circulation
• upregulate S1PR1
• ability to re-enter lymphoid tissue is reduced
  (decrease in CCR7, L-selectin)
• Increased ability to enter inflammed tissue due
  to increased expression of
• ligands for E- and P- selectins
• receptors for inflammatory chemokines (e.g.
  CXCR3)
• adhesion molecules (e.g. integrin ????)