LYMPHOCYTE TRAFFIC
LYMPHOCYTE TRAFFIC
The lymphatic and
circulatory systems are intimately related, and there is a constant movement of
lymphocytes throughout the body, moving from one system to another. Different
subsets of lymphocytes migrate differentially into different tissues. This
process is called trafficking, or homing .
Afferent
lymphatic vessels mediate the transport of antigen and leukocytes from interstitial spaces drain into lymph
nodes, which “filter” these fluids, removing foreign substances. Afferent lymphatics are blind-ended vessels that permeate
the tissues and selectively convey lymphocytes and antigen-presenting accessory
cells into the subcapsular and medullary sinuses of lymph nodes. Meanwhile, Efferent vessels carry the clean fluid
away and back to the bloodstream where it helps form plasma. Efferent lymphatics (usually only one or two
for each node) carry lymphocytes and lymph plasma out of lymph nodes ultimately
into the major efferent ducts and then back to the blood. Efferent lymph from
regional lymph nodes may pass through one or more lymph nodes downstream before
reaching a major efferent duct. Efferent
lymph contains >98% lymphocytes with a higher proportion of B cells
and much higher flow and cell output rates than in afferent lymph. Greater than 90% of efferent lymphocytes are derived from
the blood via high endothelial venules(HEV). The same routes are traveled by lymphocytes stimulated in the
lymph nodes or peripheral lymphoid tissues, which will eventually reach the
systemic circulation. Under physiological conditions, there are profound
differences between afferent and efferent lymph flow rates, cell content and
activation status of the cells .
Peripheral blood, in turn, is “filtered” by
the spleen and liver, the spleen having organized lymphoid areas while the liver
is rich in Kupffer’s cells,which are macrophage-derived phagocytes. Organisms
and antigens that enter directly into the systemic circulation will be trapped
in these two organs, of which the spleen plays the most important role as a
lymphoid organ
The different
trafficking patterns of lymphocyte subsets are
mediated by unique combinations of adhesion molecules and chemokines; receptors
that direct the circulation of various populations of lymphocytes to particular
lymphoid and inflammatory tissues are called homing receptors. Researchers have identified a
number of lymphocyte and endothelial cell-adhesion molecules that participate
in the interaction of lymphocytes with HEVs (High endothelial
venules ), and with
endothelium at tertiary sites or sites of inflammation . Chemokines, these
molecules also play a major role in
determining the heterogeneity of lymphocyte circulation patterns.
.
A. Lymphocyte
Recirculation and Extravascular Migration
One of the most important biological characteristics of
B and T lymphocytes is their constant
recirculation, entering the lymphoid tissues to circulate through the vascular
system, enter again the lymphoid tissues, or exit into the interstitial tissues
if an inflammatory reaction is taking place.
Lymphocytes
circulating in the systemic circulation eventually enter a lymph node, exit the
systemic circulation at the level of the
high endothelial venules (HEV), leave
the lymph node with the efferent lymph, and eventually reenter the systemic
circulation.
B lymphocytes of
mucosal origin circulate between
different segments of the mucosal-associated lymphoid tissues, including the
GALT, the mammary gland–associated lymphoid tissue, and the lymphoid tissues
associated with the respiratory tree and urinary tract.
The
crucial step in the traffic of lymphocytes from the systemic circulation to a lymphoid
tissue or to interstitial tissues is the
crossing of the endothelial barrier by diapedesis at specific locations.
Under physiological conditions, this seems to take place predominantly at the level of the high endothelial venules
of lymphoid tissues. These specialized endothelial cells express surface
molecules—cell adhesion molecules (CAMs)—which interact with ligands,
including other cell adhesion molecules, expressed on the membrane of T and B
lymphocytes. The interplay between
endothelial and lymphocyte CAMs determines the traffic and homing of
lymphocytes. Cell adhesion molecules are also upregulated during
inflammatory reactions and determine the extravascular migration of lymphocytes
and other white blood cells.
B. Cell Adhesion
Molecules
Three main families of
cell adhesion molecules are as follows:
Ø The addressins
or selectins are expressed on endothelial cells and leukocytes and mediate
leukocyte adherence to the endothelium.
Ø The
immunoglobulin superfamily of CAMs includes a variety of molecules expressed by leukocytes,
endothelial cells, and other cells.
Ø The integrins
are defined as molecules that interact with the cytoskeleton and tissue matrix
compounds.
The following CAMs
have been reported to be involved in lymphocyte traffic and homing:
LAM-1, ICAM-1, and
CD44 are primarily involved in controlling
lymphocyte traffic and homing in peripheral lymphoid tissues.
MadCAM-1 is believed
to control lymphocyte homing to the
mucosal lymphoid tissues.
The interaction
between adhesion molecules and their
ligands takes place in several stages.
First, the cells adhere to endothelial cells at the level of the high endothelium venules (HEV), and the adhering lymphocyte is able then to migrate through endothelial slits
into the lymphoid organ parenchyma. Different CAMs and ligands are involved
in this sequence of events.
Regulation
of Lymphocyte Traffic and Homing
The way in which cell adhesion molecules regulate lymphocyte
traffic and homing seems to be a result both of differences in the level of
their expression and of differences in the nature of the CAM expressed in
different segments of the microcirculation.
The involvement of HEV
as the primary site for lymphocyte outlet from the systemic circulation is a
consequence of the interaction between
CD34, a specific CAM expressed in HEV, and L-selectin, expressed by naive T
lymphocytes. Because CD34 is
predominantly expressed by HEV, the opportunity for cell adhesion and
extravascular migration is considerably higher in HEV than on segments of the
venous circulation covered by flat endothelium.
It is known that the lymphocyte constitution of lymphoid organs
is variable . T lymphocytes predominate
in the lymph nodes, but B lymphocytes and IgA-producing plasma cells
predominate in the Peyer’s patches and the GALT in general. This differential
homing is believed to be the result of
the expression of specific addressins such as MadCAM-1 on the HEV of the
perimucosal lymphoid tissues, which are specifically recognized by the B cells
and plasma cells resident in those tissues. Most B lymphocytes recognize
specifically the GALT-associated HEV and do not interact with the lymph node–associated
HEV, while most naive T lymphocytes recognize both the lymph node–associated
HEV and the GALT-associated HEV.
The differentiation of
T-dependent and B-dependent areas in lymphoid tissues is a poorly understood
aspect of lymphocyte “homing.” It appears likely that the distribution of T and B lymphocytes is determined by their interaction
with nonlymphoid cells. For example, the interaction between
interdigitating cells and T lymphocytes may determine the pre-dominant location
of T lymphocytes in the lymph node paracortical areas and
periarteriolar sheets of the spleen, while the interaction of B
lymphocytes with follicular dendritic cells may determine the organization of
lymphoid follicles in the lymph node, spleen, and GALT.
The modulation of CAM at different states of
cell activation explains changing patterns in lymphocyte recirculation seen
during immune responses. Immediately after antigen stimulation, the
recirculating lymphocyte appears to transiently lose its capacity to
re-circulate. This loss of recirculating
ability is associated with a tendency to self-aggregate (perhaps explaining
why antigen-stimulated lymphocytes are trapped at the site of maximal antigen
density), due to the upregulation of
CAMs involved in lymphocyte-lymphocyte and lymphocyte–accessory cell
interactions.
After the antigenic stimulus ceases, a
population of memory T lymphocytes carrying distinctive membrane proteins can
be identified. This population
seems to have a different recirculation
pattern than that of the naive T lymphocyte, leaving the intravascular compartment at sites other than the HEV and
reaching the lymph nodes via the lymphatic circulation. This difference in
migration seems to result from the
downregulation of the CAMs, which mediate the interaction with HEV
selectins, and upregulation of other CAMs, which interact with selectins
located in other areas of the vascular tree.
B lymphocytes also change their recirculation patterns after antigenic
stimulation. Most B cells will
differentiate into plasma cells after stimulation, and this differentiation
is associated with marked changes in the antigenic composition of the cell
membrane. Consequently, the plasma cell
precursors (plasmablasts) exit the germinal centers and move into the medullary
cords and, eventually, to the bone marrow, where most of the antibody
production in humans takes place. Another B-cell subpopulation—the memory B
cells— retain B cell markers and reenter
the circulation to migrate back to specific territories of the lymphoid tissues.
All memory lymphocytes, T or B, appear to home preferentially in on the type of lymphoid tissue where the
original antigen encounter took place, i.e., a lymphocyte that recognizes
an antigen in a peripheral lymph node will recirculate to the same or another peripheral lymph node, while a lymphocyte
that is stimulated at the GALT level will recirculate to the GALT. Memory B
lymphocytes remain in the germinal centers, while memory T lymphocytes home in
on T-cell areas.
Inflammatory and immune reactions often lead
to the release of mediators that up-regulate the expression of CAM in venules
or in other segments of the microvasculature near the area where the reaction
is taking place. This results in a
sequence of events that is mediated by different sets of CAMs and their respective ligands.
Ø First the leukocytes slow down and start rolling along the endothelial surface. This stage
is mediated primarily by selectins.
Ø Next,
leukocytes adhere to endothelial cells expressing integrins such
as VLA and CAMs of the immunoglobulin superfamily, such as ICAM and VCAM.
Ø Finally, the adherent leukocytes squeeze between two adjoining endothelial cells and
move to the extravascular space.
The end result of this
process is an increase in leukocyte
migration to specific areas where those cells are needed to eliminate some type
of noxious stimulus or to initiate an immune response. As a corollary,
there is great interest in developing compounds able to block upregulated CAMs
to be used as anti-inflammatory agents.
Reference
Lymphocyte Traffic.” BrainKart,
http://www.brainkart.com/article/Lymphocyte-Traffic_21543/. Accessed 25 Nov.
2021.
Owen, Judith, et al. Kuby
Immunology. 7. ed., International ed, Macmillan Higher Education, 2013.
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