Editors' ChoiceImmunology

Keeping T cells in place

Sci. Signal.  12 May 2015:
Vol. 8, Issue 376, pp. ec125
DOI: 10.1126/scisignal.aac5398

To mediate inflammation, T cells must leave the circulation by migrating across the endothelial cell layer that lines blood vessels and entering the affected tissue. Chimen et al. (see also the commentary by Saba) found that the adipokine adiponectin induced the release of a peptide from B cells that inhibited the transendothelial migration of T cells in a mechanism that required the lipid mediator sphingosine-1 phosphate (S1P). Adiponectin inhibited the migration of human peripheral blood lymphocytes (PBLs) across endothelial cell monolayers in response to TNF-α (tumor necrosis factor–α) and IFN-γ (interferon-γ). Adiponectin receptors were abundant on B cells, but not on most T cells, and supernatants from adiponectin-stimulated B cells inhibited the migration of PBLs to a similar extent as did adiponectin. A proteomic screen identified a peptide corresponding to a proteolytic cleavage product of 14-3-3ζδ protein that was found only in the supernatants of adiponectin-stimulated B cells, which the authors called PEPITEM (peptide inhibitor of transendothelial migration) and which bound to cadherin-15 (CDH15) on endothelial cells. Application of a synthetic version of this peptide inhibited the migration of PBLs across endothelial cell monolayers, which required the production of S1P by sphingosine kinase 1 (SPHK1) from endothelial cells, the export of S1P from endothelial cells, and functional S1P receptors on T cells. PEPITEM attenuated T cell trafficking into the peritoneum of mice with zymosan-induced peritonitis, the hepatic sinusoids of mice with acute liver ischemia and reperfusion injury, and other tissues in various pathological contexts. Uncontrolled T cell tissue infiltration can lead to autoimmune diseases, and in B cells from individuals with type 1 diabetes or rheumatoid arthritis, the cell surface abundance of the adiponectin receptors adipoR1 and adipoR2 was reduced, which correlated with decreased release of PEPITEM. B cells from individuals with type 1 diabetes or rheumatoid arthritis did not inhibit PBL migration across endothelial cell monolayers, an effect that was rescued with exogenous PEPITEM. Thus, adiponectin restricts T cell trafficking by stimulating B cells to release a 14-3-3ζδ fragment that promotes S1P secretion from endothelial cells.

M. Chimen, H. M. McGettrick, B. Apta, S. J. Kuravi, C. M. Yates, A. Kennedy, A. Odedra, M. Alassiri, M. Harrison, A. Martin, F. Barone, S. Nayar, J. R. Hitchcock, A. F. Cunningham, K. Raza, A. Filer, D. A. Copland, A. D. Dick, J. Robinson, N. Kalia, L. S. K. Walker, C. D. Buckley, G. B. Nash, P. Narendran, G. E. Rainger, Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease. Nat. Med. 21, 467–475 (2015). [PubMed]

J. D. Saba, A B cell–dependent mechanism restrains T cell transendothelial migration. Nat. Med. 21, 424–426 (2015). [PubMed]