Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation.
Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation.
Department of Cell Biology, Duke University Medical Center, Durham NC 27710, USA.
Sambuddho
S
Mukherjee
Charles
C
Giamberardino
Joseph
J
Thomas
Kathy
K
Evans
Hisatsugu
H
Goto
Julie G
JG
Ledford
Bethany
B
Hsia
Amy M
AM
Pastva
Jo Rae
JR
Wright
D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency / Q000494:pharmacology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D008070:Lipopolysaccharides; D008934:Mitogens; D037662:Pulmonary Surfactant-Associated Protein A; D002118:Calcium