Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation

Activated T cells acquire the ability to home to extralymphoid sites, including the lungs, skin, gastrointestinal tract and central nervous system, where they can enter extravascular tissues even in the absence of inflammation. They can also enter almost any site of inflammation.Activated effector and central memory T cells use selectins and selectin ligands to enter some of these sites: most prominently E-selectin for the skin, L-selectin for the inflamed pancreas and salivary glands, and P-selectin for the lamina-propria compartment of the gastrointestinal tract.All T cells express P-selectin glycoprotein ligand 1 (PSGL1), but PSGL1 is not functional in naive T cells, in which the necessary glycosyltransferases are not expressed. Regulated glycosyltransferases in T cells include fucosyltransferase-VII (FucT-VII), core 2 β1,6-glucosaminyltransferase-I (C2GlcNAcT-I) and sialyl 3-galactosyltransferase-IV (ST3Gal-IV).T helper 1 (TH1) cells express more FucT-VII, C2GlcNAcT-I and ST3Gal than TH2 cells and bind E-selectin much better, but some TH2 cells can also bind E-selectin. FucT-VII is the limiting enzyme for E-selectin-binding activity, which is detected by binding of monoclonal antibody HECA-452, whereas C2GlcNAcT-I determines P- and L-selectin-ligand activity in T cells.FucT-VII and C2GlcNAcT-I are independently regulated. Whereas FucT-VII is expressed after T-cell receptor ligation through a RAS-dependent pathway with additional signals from the interleukin-12 receptor (IL-12R) through unknown signalling molecules, C2GlcNAcT-I is under the control of the IL-12R through signal transducer and activator of transcription 4 (STAT4).Naive T cells express L-selectin, but cannot enter most extralymphoid sites. Some T cells, including central memory cells, re-express L-selectin after antigen encounter and can home to sites of chronic inflammation, where the L-selectin ligand peripheral node addressin (PNAD), detected by monoclonal antibody MECA-79, is expressed through the induction of high endothelial cell (HEC)-GlcNAc6ST expression, especially in inflamed exocrine and endocrine glands.Endothelial cells express P- and E-selectin constitutively in the skin and inducibly in many organs during acute and chronic inflammation. At sites of inflammation, T-cell interactions are likely to involve selectin-dependent interactions with myeloid leukocytes, platelets, and leukocyte- and platelet-derived microparticles, which complicate the interpretation of experiments using knockout mice or antibody blockade of selectins or their ligands.