Topic 2 lecture note..

L, M, X, D, and E integrins are major receptors of the immune system
A subgroup of 2 integrins
The four -subunits of this subgroup assemble with the integrin 2-subunit to generate
the integrins L2 (LFA-1, CD11a/CD18), M2 (Mac-1, Mo-1, CR3, CD11b/CD18),
X2 (p150,95, CR4, CD11c/CD18), and D2 (CD11d/CD18) (Springer, 1995). They
are restricted to leukocytes, where L2 is expressed by most leukocytes, and M2 and
X2 are on monocytes/macrophages, granulocytes, large granular lymphocytes, and a
subpopulation of immature B cells. X2 is also present on some activated T cells.
L2: L2 mediates the adhesion of leukocytes to the intercellular adhesion molecules
ICAM-1, ICAM-2, and ICAM-3, which are inducibly or constitutively expressed on
many cell types. It participates in leukocyte transendothelial migration, recirculation,
homing, and localization to inflammatory sites. L2 plays a key role in antigenpresentation,
T-cell costimulation, the cytotoxicity of T cells, delayed-type
hypersensitivity, and endotoxin shock.
Leukocytes from mice lacking L display defects in in vitro homotypic aggregation, in
proliferation in mixed lymphocyte reactions, and in response to mitogen. In vivo, host-vsgraft
reaction toward injected allogeneic cells is also reduced. Neutrophils and activated
T lymphocytes are unable to cross endothelial cell monolayers in response to a
chemokine gradient. The trafficking of lymphocytes to peripheral lymph nodes, and, to a
lesser degree, to mesenteric lymph nodes and acute inflammatory sites is impaired.
Mutant mice mounted normal cytotoxic T cell (CTL) responses against systemic LCMV
and VSV infections, and showed normal ex vivo CTL function. However, they did not
reject immunogenic tumors grafted into footpads, and did not demonstrate priming
response against tumor-specific antigen. Thus L deficiency causes a selective defect in
induction of peripheral immune responses, whereas responses to systemic infection are
normal.
M2 and X2: M2 interacts with an assortment of ligands including ICAM-1,
iC3b, fibrinogen, serum factor X, and heparin, and may bind denatured proteins,
deoxyoligonucleotides, elastase, high molecular weight kininogen, and carbohydrate -
glucan structures. It interacts with the 3 rd Ig domain of ICAM-1, whereas L2 interacts
with the 1 st Ig domain. When L2 and M2 are expressed at similar levels, the L2
/ICAM-1 interaction dominates over the M2/ICAM-1 interaction.X2 binds to iC3b,
fibrinogen, and ICAM-1. M2 and X2 mediate myeloid cell adhesion to
endothelium, transmigration, chemotaxis, phagocytosis of opsonized particles, and
respiratory burst. M2-deficient mice have significant reductions in the numbers of
mast cells resident in the peritoneal cavity, peritoneal wall, and dorsal skin. Such mice
exhibit significantly increased mortality to acute septic peritonitis, where host resistance
depends on both mast cells and complement.
D2: D2 binds preferentially to ICAM-3. The D subunit is more closely related to
M and X than to L. D2 is expressed at moderate levels on myelomonocytic cell
lines, and subsets of peripheral blood leukocytes. It is strongly expressed on tissue-