Lymphocyte Activation

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Lymphocyte Activation Recognition David
Straus dbstraus_at_vcu.edu Reading Chpt 8-2,
8-3, 8-4, 8-11, 10-6
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T cell activation proliferation differentiation
Activation of naïve T cells leads to their
proliferation and differentiation into effector
cells
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Proliferation is essential to expand the numbers
of antigen-specific lymphocytes and provide an
effective immune response
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Differentiation of naïve cells is necessary to
provide effector function and regulate the nature
of the immune response
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A recognition problem How do you find the
lymphocyte with the correct specificity?
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Activation occurs in lymph nodes
Lymphocytes are activated in lymph nodes near the
site of infection. Following activation, effector
T cells migrate to the site of infection, and
antibodies are carried through the blood and
lymph.
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Figure 2-41
Low specificity interactions mediated by
chemokines and adhesion molecules direct the
trafficking of lymphocytes. Chemokines and
chemokine receptors tell lymphocytes where to
stop during circulation and where to go within
tissues and lymphoid organs.
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Cells with the appropriate receptors will move
toward the source of a chemokine.
Chemokine gradient
Movement is mediated by polarized actin
reorganization
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Adhesion molecules mediate intercellular
interactions
Intercellular interactions are mediated by
adhesion molecules selectins, integrins, and Ig
superfamily proteins
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Selectins
Selectins recognize specific carbohydrate
modifications. Selectin expression is determined
by cell type and activation state. Naïve T cells
express L-selectin.
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Inegrins
Integrins are expressed as a and b dimers which
can bind a variety of protein ligands, including
Ig superfamily members. Integrin activity is
controlled by regulated expression and affinity.
LFA-1 is one of the integrins expressed on T
cells.
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Ig Superfamily
Ig superfamily members are defined by the
presence of a protein domain found in
immunoglobulin molecules. Many Ig proteins are
ligands for integrins.
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T cell homing to lymph nodes or to sites of
infection is determined in part by the selective
expression and activity of specific
chemokines/chemokine receptors and adhesion
molecules
CCR7
CX3CR3
LFA-1
CXCL10
CCL21
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Entry of naïve T cells into the lymph node
depends upon three discrete steps rolling,
stopping and diapedesis
How does naïve T cell entry into lymph nodes
differ from neutrophil recruitment to sites of
inflammation?
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Analysis of C-C chemokine receptor 7(CCR7) -/-
mice
Forster, R., et al. Cell 99 23 (1999).
(splenocytes)
ELC - CCR7 ligand SDF - CXCR4 ligand
PBL Spl BM MLN PLN
Forster, et al. 1999. Cell 9923
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Analysis of C-C chemokine receptor 7(CCR7) -/-
mice
Figure 2
Figure 5
Forster, et al. 1999. Cell 9923
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Within the lymph node, naïve T cell interaction
with antigen presenting cells is initiated
through interaction of adhesion molecules
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TCR signals enhance integrin binding
Affinity of integrin interaction is enhanced
following successful antigen receptor engagement
- inside-out signaling
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Specificity of T lymphocyte activation relies
upon TCR recognition of MHC-peptide a relatively
low affinity interaction compared to
immunoglobulin.
TCR
MHC- peptide
TCR
MHC I
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TCR binds both MHC and peptide
The T cell antigen receptor (TCR) recognizes
determinants on both the specific peptide and the
MHC molecule
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CD4/8 coreceptors
CD4 and CD8 molecules act as co-receptors they
recognize MHC II or MHC I, and help stabilize the
TCR-MHC interaction by forming a tripartite
complex
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CD28 provides 2nd signal
Additional receptor-ligand interactions, e.g.
CD28 - B7, enhance T cell activation following
APC binding.
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Molecular rearrangements w/synapse formation
T cell receptor engagement with MHC-peptide
induces reorganization of cell surface molecules.
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Synapse w/scanning EM
Re-organization of molecules on the cell surface
generates an immune synapse which can be
analyzed by fluorescence microscopy
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Figure 8-29
Immune synapse formation allows the directed
release of effector molecules -cytokines and
cytotoxic granules, as well as providing a stable
interaction with APCs necessary for activation of
naïve T cells.
Cytoskeleton green Lytic granules red
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Using fluorescently labeled ligands to assess
receptor partitioning following antigen receptor
engagement
 The mature immunological synapse. Patterns of
LFA-1 ( A), TCR ( B), and CD28 ( C) interaction
in a functional synapse between a T cell and a
supported planar bilayer containing Cy5-ICAM-1,
Oregon Green-I-A k, and Cy3-B7. All three
markers are overlaid in panel D with the cSMAC
and pSMAC labeled. SMAC supramolecular
activation complex
Bromely, et al. 2001. Ann. Rev. Imm. 19375
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Question for discussion
You have identified two new vertebrate organisms
with novel immune system anatomy, the first
organism has only has a single secondary lymphoid
organ, while the second is identical in size to
humans but has ten times the number of lymph
nodes. A). In the organism with a single
secondary lymphoid organ, naïve T cells do not
circulate. This organ is identical in structure
and function to a human lymph node. Naïve T
cells are distributed normally within the organ,
and it is the site of lymphocyte activation.
However, evolution has led to changes in naïve T
cell surface molecules involved in circulation
functions that are no longer required have been
lost. What do you expect will have happened to
the expression of L-selectin, chemokine receptor
CCR7, and integrin LFA-1? For each case explain
your answer. B). The second organism, with many
more lymph nodes than humans, has an innate and
adaptive immune system that uses the same
mechanisms and has the same number of cells as in
humans. What impact do you expect the increased
number of lymph nodes to have on the initiation
of an adaptive immune response? Explain your
answer.