Glycodelin-A interferes with IL-2/IL-2R signalling to induce cell growth arrest, loss of effector functions and apoptosis in T-lymphocytes.
BACKGROUND
The progesterone-regulated glycoprotein glycodelin-A (GdA), secreted by the decidualized endometrium at high concentrations in primates, inhibits the maternal immune response against fetal antigens and thereby contributes to the tolerance of the semi-allogenic fetus during a normal pregnancy. Our earlier studies demonstrated the ability of GdA to induce an intrinsic apoptotic cascade in CD4(+) T-lymphocytes and suppress the cytolytic effector function of CD8(+) T-lymphocytes. In this report, we investigated further into the mechanism of action of GdA controlling perforin and granzyme B expression in CD8(+) T-lymphocytes and the mechanism of action of GdA leading to lymphocyte death.


METHODS
Flow cytometry analysis was performed to check for the surface expression of interleukin-2 receptor α (IL-2Rα) and intracellular eomesodermin (Eomes) in activated T-lymphocytes, whereas quantitative RT-PCR analysis was used to find out their mRNA profile upon GdA treatment. Western analysis was carried out to confirm the protein level of Bax and Bcl-2.


RESULTS
GdA reduces the surface expression of the high-affinity IL-2R complex by down-regulating the synthesis of IL-2Rα (CD25). This disturbs the optimal IL-2 signalling and decreases the Eomes expression, which along with IL-2 directly regulates perforin and granzymes expression. Consequently, the CD8(+) T-lymphocytes undergo growth arrest and are unable to mature into competent cytotoxic T-lymphocytes. In the CD4(+) T-lymphocytes, growth factor IL-2 deprivation leads to proliferation inhibition, decreased Bcl-2/enhanced Bax expression, culminating in mitochondrial stress and cell death.


CONCLUSIONS
GdA spurs cell cycle arrest, loss of effector functions and apoptosis in different T-cell subsets by making T-lymphocytes unable to respond to IL-2.
Department of Biochemistry,  Indian Institute of Science, Bangalore 560012,  India.
Chetna
C
Soni
Anjali A
AA
Karande
D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D005434:Flow Cytometry; D000071816:Glycodelin; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; C491199:EOMES protein, human; D000071816:Glycodelin; D006023:Glycoproteins; D007376:Interleukin-2; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D020825:T-Box Domain Proteins; D051028:bcl-2-Associated X Protein