T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 224

When antigens are associated with an inflammatory stimulus, they
trigger maturation and migration of DCs to tissue draining lymph nodes,
where these cells produce IL-12 and induce development of Th-1 cells
(124-126). IL-12-mediated induction of IFN-g expression in T-cells is regu-
lated by the transcription factor STAT-4 and T-box expressed in T-cells
(T-bet) (127). Phosphorylation of STAT-4 is crucial for STAT-4 activation
and translocation to the nucleus (128). Thus, IL-12 = STAT-4 serves two
essential functions in the development of activated Th-1 cells: as a growth
signal-inducing survival and cell division and as a transactivator prolonging
IFN-g synthesis (129-131). It has recently been shown that CD4 þ T-cells in
smokers' lungs express phosphorylated STAT-4 and this was associated
with the presence of IFN-g in these cells indicating that they are activated
effector CD4 þ T-cells (89).
Homing receptor regulation during memory effector T-cell differentia-
tion is analogous to (and temporally concomitant with) effector T-cell cyto-
kine production (i.e., IFN-g, IL-2 in the helper Th-1 subset) involving
immunoregulatory cytokines, as well as the nature of antigenic and costimu-
latory signals (132). As lymphocytes must be positioned correctly to interact
with other cells, the pattern of chemokine receptors, and the type and
distribution of chemokines in tissues, will critically influence immune
response (133-136). Imprinting, or selection, for tissue differential homing
properties is determined by the local lymphoid organ microenvironment
and begins almost immediately during the na¨ve-to-memory = effector T-cell
transition, within one to two cell divisions in intestine-associated lymphoid
tissues (137).
Recent studies have reported that T-cells trafficking to the human lung
are distinct from either gut-homing or skin-homing T-cells and express che-
mokine receptors CXCR3, CCR5, and CCR4 (138). The production of che-
mokine receptors CXCR3 ligands IFN-g-inducible protein-10 (IP-10),
monokine induced by IFN-g (Mig), and IFN-inducible T-cell chemoattrac-
tant (I-TAC) are specifically activated by IFN-g and have critical roles in
enhancing Th-1 T-cell recruitment and activation (139,140). Concomitant,
preferential expression of the associated chemokine receptors on Th-1
T-cells has been demonstrated (141-143). Thus chemokine expression dur-
ing a Th-1 response correlates directly with the specificity of the chemokine
receptors expressed on Th-1 T-cells.
The function of these chemokines, induced in tissue by the T-cell acti-
vation, together with selectins and integrins, would be the extravasation and
migration of leukocytes that express a large repertoire of chemokine recep-
tors. These molecules exert most of their biological effects by binding to a
large family of G-protein-coupled seven transmembrane receptors leading
to activation of multiple intracellular signaling pathways (144). In addition
to promoting leukocyte migration, chemokines are potent cellular activators
(145,146).