Transfer experiments using OT-II transgenic T cells, which are specific for an ovalbumin peptide, revealed that T cells that had undergone multiple rounds of cell division up-regulated S1P1 and down-regulated CCR7, and cells that had undergone a high number of divisions were more frequently found in the circulation.[24] Presumably, this would allow effector cells to exit the lymph node and scan the periphery

for antigen. Similarly, transgenic mice over-expressing S1P1 in T cells had increased T cells in blood, had elevated IgE before and after immunization, and selleck compound exhibited aberrant activation profiles in delayed-type hypersensitivity responses, including decreased cell recruitment to the site of inflammation and lower surface CD69 expression by lymph node T cells.[29] These studies suggest that proper cell activation is a function of cell localization, and a model constructed from balancing lymph node retention Autophagy inhibitor cell line versus escape mechanisms demonstrates that these signals dictate lymphocyte dwell time within the lymph node, potentially

affecting the generation of the adaptive immune response.[30, 31] Sphingosine-1-phosphate receptor 1 is coupled to Gαi, and is therefore pertussis-toxin-sensitive. Signals from S1P1 are transduced via multiple downstream pathways, including mitogen-activated protein kinase, phospholipase C, phosphoinositide 3 kinase/Akt and adenylyl cyclase.[32] Activation of these different signalling cascades

is known to result in diverse biological outcomes; however, their applicability to T-cell biology is, in some cases, unknown. For instance, Akt-mediated phosphorylation of S1P1 RG7420 solubility dmso is required for Rac activation and chemotaxis in endothelial cells, yet it is unclear if this same mechanism is active within T cells.[33] Phosphoinositide 3 kinase and mammalian target for rapamycin are known to affect T-cell trafficking by regulating Kruppel-like factor 2 (KLF2) expression.[34] KLF2 is a transcription factor that can modulate expression of CD62L (l-selectin), CCR7 and S1P1[35, 36] and may maintain T-cell quiescence, as its loss results in unrestrained expression of inflammatory chemokine receptors.[37] Phosphoinositide 3 kinase and/or mammalian target for rapamycin inhibition resulted in higher expression of KLF2, CD62L, CCR7 and S1P1. Lymph node homing chemokine receptors such as CCR7 and CD62L are expressed on naive T cells and are lost on T effector cells, which home to tissues to fight infection.[30] It is unclear how CCR7 is lost while S1P1 surface expression increases when expression of both factors are controlled by KLF2, although post-translational modifiers and protein–receptor interactions may be involved. It is also possible that transcription of S1P1 or CCR7 can be initiated by other transcription factors, since expression of both receptors is dependent on the T-cell developmental stage as well as phenotype and location.