Getting together in germinal centers

In this issue of Science Immunology, Gallman et al. reveal how S-geranylgeranyl-l-glutathione cleavage and transport support P2RY8-driven B cell confinement to the germinal centers and its role in lymphocyte homing to the bone marrow.

Tyrosine sulfation and O-glycosylation of chemoattractant receptor GPR15 differentially regulate interaction with GPR15L

GPR15 is a G protein-coupled receptor (GPCR) that directs lymphocyte homing to the colon and skin. Recent studies have identified a chemokine-like protein C10orf99/GPR15L as a functional ligand of GPR15. In this study we examined the structural elements that regulate the GPR15-GPR15L interaction with primary focus on post-translational modifications (PTMs) of receptor N-terminus and on the C-terminus of the ligand. Our findings reveal that the GPR15 receptor is sulfated on the N-terminal Tyr residue(s) and disruption of Tyr sulfation inhibited binding of GPR15L. In contrast, the disruption of O-glycosylation on the N-terminal Thr/Ser residues or the removal of α2,3-linked sialic acids from O-glycans enhanced the GPR15L binding. Thus, GPR15 represents a unique chemoattractant receptor in which different N-terminal PTMs regulate its ligand binding in a contrasting manner. We further demonstrate that unlike canonical chemokines, GPR15L activity critically requires its extreme C-terminal residue and its hydrophobicity may be a key attribute that facilitates an optimal interaction with the receptor. Our results reveal novel insights into chemoattractant receptor-ligand interaction and provide a valid footing for potential intervention targeting GPR15-GPR15L axis.

Exosomal regulation of lymphocyte homing to the gut

Exosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4β7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4β7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4β7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.

Transmission of integrin β7 transmembrane domain topology enables gut lymphoid tissue development

Integrin activation regulates adhesion, extracellular matrix assembly, and cell migration, thereby playing an indispensable role in development and in many pathological processes. A proline mutation in the central integrin β3 transmembrane domain (TMD) creates a flexible kink that uncouples the topology of the inner half of the TMD from the outer half. In this study, using leukocyte integrin α4β7, which enables development of gut-associated lymphoid tissue (GALT), we examined the biological effect of such a proline mutation and report that it impairs agonist-induced talin-mediated activation of integrin α4β7, thereby inhibiting rolling lymphocyte arrest, a key step in transmigration. Furthermore, the α4β7(L721P) mutation blocks lymphocyte homing to and development of the GALT. These studies show that impairing the ability of an integrin β TMD to transmit talin-induced TMD topology inhibits agonist-induced physiological integrin activation and biological function in development.