Transcript Why chemokines?

Orchestrating the orchestrators:
chemokines in control of T cell traffic
December 20th 2010
Kathrin Hüging
Why chemokines?
• Chemokines
– are small chemoattractant proteins
– stimulate the migration and activation of cells, especially
phagocytic cells and lymphocytes
– are secreted molecules,
• in vivo they are “seen“ by leukocytes while bound to extracellular matrix molecules
or to cell surfaces via proteoglycans
– serve a central function in the immune system by coordinating the localization
of immune cells in the body to generate an immune response at specific
anatomic sites
– Regulate cell motility and cell adhesion through ligation of G protein-coupled
receptors expressed on leukocytes
Migration of naive T cells to secondary lymphoid organs
• After thymic selection, only naive cells
that encounter cognate antigen in
defined molecular contexts terminally
differentiate into effector cells
– secondary lymphoid organs (SLOs)
have evolved as specialized stromal
environments
 facilitate this process
• SLO function depends on:
– Recruitment of cells from the bloodstream
– Cell migration through SLO microenvironments
– Egress and migration to other SLOs
Controlled by chemokines
Molecular Biology of the Cell. 3rd edition.
Chemokines and T cell entry into lymph nodes
• CCL21 (& CCL19):
– CCR7 ligand
– Mainly produced by stromal
cells
– Deposited on
• FRCs (fibroblastic reticular
cells)
• HEVs (high endothelial
venules)
– Triggers integrin-dependent
firm adhesion of rolling naive
and central memory T cells
– Possibly triggers haptotactic
(directed) or hatpokinetic
(nondirected) diapedesis
through the endothelium
 Entry into lymph node
haptokinesis= substrate dependent migration along an adhesion gradient
(immobilized ligand)
Chemokines and T cell migration along stromal networks
• CCR7 ligands are critical for the
proper organization of SLOs into
– B cell follicles
– T cell areas
• CCL21 promotes haptokinetic
migration along the stromal
reticulum
 allows efficient scanning of DCs
associated with this network
(stochastic exploration)
Chemokines and T cell egress from lymph nodes
• In the absence of foreign antigens
stimulation, T cells eventually
become sensitive to molecular
“exit“ cues
• S1P:
– Sphingosine 1-phosphate
– Lipid G protein-coupled receptor
agonist
– Coordinates lymph node egress
•  T-cell egress is controlled by
competing signals from CCR7
ligands and S1P
Chemokines and reactive lymph nodes
• Additional function of lymph
nodes during adaptive immune
response:
– Shaping the quality of the
response
– Controlling magnitude and
duration of the immune
response
 Other chemokines serve to
broaden the variety of cell
populations recruited from the
bloodstream and to orchestrate
cellular collaborations
Chemokines and reactive lymph nodes
• Downregulation of CCR7 ligands
• CXCR 3 ligands (CXCL9 & 10) appear
– Recruitment of differentiated effector
T-cells
• CCL3 & 4 are produced at sites of
cognate interactions of DCs with
CD4+ helper T-cells (guided
encounters)
– might also facilitate interaction with
CD8+ T cells (tricellular encounters)
• Lymph node shutdown (transient
decrese of lymph node egress) and
enhanced homing of T cell
 accounts for the initial increase in
lymph node cellularity
Chemokine guidance into peripheral tissue
• Naive lymphocytes circulate mainly among SLOs
• Antigen-experienced lymphocytes upregulate various combinations of
adhesion, chemokine and lipid chemoattractant receptors
– Specific combination allows T cells to interact with blood vessel
endothelium and to migrate into and within distinct peripheral tissues
– e.g. CCR9: small intestine; CCR4 & CCR10: skin
 surveillance and response to inflammatory stimuli
•
Lymphocyte trafficking may become less restricted in conditions of
inflammation
 tissue-specific vs. inflammation-induced chemokine and adhesion
receptors
Innate NKT and γδ T cells
• During an immune response, distinct T cell subsets are generated in
the lymphoid compartment
• Chemokines guide these subsets into sites of inflammation and
infection
• Before the generation of antigen-specific T cell subsets, NKT and
γδ T cells ( „innate T cells“) provide the first line of host defense
• Are also guided to sites of inflammation and infection by
chemokines
• Receptor expression patterns suggests different trafficking
potentials
Chemokine receptors on innate NKT and γδ T cells
Chemokine receptors on T cell subsets
Polarized CD4+ T cell response may be amplified by a positive
feedback loop involving chemokines:
• After activation, naive T cells differentiate into
distinct CD4+ helper T cell subsets
– depends on the cytokine milieu
• Amplification of polarized response via
positive feedback loop:
– TH1 cells:
• Transcription factor T-bet directs both TH1 cell
differentiation and CD4+ T cell expression of
CXCR3
• INF-γ activates STAT1 in tissue-resident cells to
upregulate CXCR3 ligand expression
 recruitment of additional CXCR3-expressing,
INF-γ-secreting TH1 cells
•TH1 cells:
•subset of CD4 T cells, mainly involved in
activating macrophages (sometimes called
•
inflammatory CD4 T cells)
•TH2 cells:
Regulation especially important for Th17
response:
• mainly involved in stimulating B cells to
produce antibody, (often called helper CD4 T
cells)
•
amplification may drive many autoimmune
inflammatory conditions
Control of the feedback loop by regulatory T cells
• Depending on the cytokine
milieu in which the Treg cells are
activated, these cells might
express distinct chemokine
receptor expression profiles
– Overlap of chemokine receptor
expression profile of Treg cells
and diverse effector T cell
subsets
 Should allow Treg cells to
localize together with diverse
effector T cells to control the
immune response
•
Better understanding of this
mechanism should allow therapeutic
targeting to treat inflammatory
conditions
Conclusion
• Chemokine system orchestrates T cell migratory patterns to
generate, deliver and regulate specific types of immune
responses in specific anatomic microenvironments
• Controls T cell trafficking in the lymphoid compartment and
in peripheral tissue
• To allow therapeutic interference with this system, a deeper
understanding of chemokine function is needed:
• How do chemokines coordinate the encounters between
different immune cells for information exchange?
• How is specificity achieved despite so much redundancy
in the chemokine system?
• What is the importance of chemokines in cellular
functions other than migration?
Questions?
Have a save trip home & a nice vacation!