No abstract

Recruitment of lymphocytes to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. Of these, the lectin-like molecule CD44 has been particularly implicated in inflammatory trafficking. Using a TNF-driven model of chronic ileitis (i.e., B6.129P-TnfΔARE mice) that recapitulates many features of Crohn’s disease, we demonstrate dynamic changes in the expression and functional state of CD44 on CD8+ T cells. These cells coexpress CD44 and L-selectin, giving them a surface phenotype similar to that of central memory T cells. Yet functionally they exhibit the phenotype of effector T cells, because they produce IFN-γ. Unexpectedly, depletion of the CD8+ population had no effect on the severity of ileitis. Further analyses showed a second CD8+ population that lacked CD44, but expressed CD103, produced TGF-β, inhibited the proliferation of CD4+ in vitro, and attenuated adoptively transferred ileitis in vivo, most likely counteracting the proinflammatory role of the CD44high subset. Collectively, these data suggest that the presence or absence of CD44 and CD103 on the CD8+ lymphocyte surface defines functionally distinct subsets of CD8+ T cells in vivo. These inflammation-driven populations exert distinct roles during the development of chronic ileitis, and influence the balance of effector and regulatory functions in the chronically inflamed small intestine.

Background & Aims Lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. In the current studies we analyzed the role of CD44 for the development of chronic small-intestinal inflammatory infiltrates in vivo. Methods By using a tumor necrosis factor (TNF)-driven model of chronic ileitis (ie, B6.129P-TNFΔAU-rich element [ARE]) that recapitulates many features of Crohn’s disease, we noticed dynamic changes in the expression and functional state of CD44 and its ligand hyaluronan via enzyme-linked immunosorbent assay, real-time reverse-transcription polymerase chain reaction, immunohistochemistry, and flow cytometry. In addition, we assessed the role of lymphocyte populations during induction of ileitis through adoptive transfer studies, and generated CD44-deficient TNFΔARE mice to assess the role of CD44 for development of ileitis. Results Soluble hyaluronan levels and expression of hyaluronan synthase-1 were increased in TNFΔARE mice. This coincided with increased expression of CD44 (including variant 7) and reactivity towards hyaluronan on CD4+ T cells. CD44 was spatially co-localized with the gut-homing integrin α4β7, spatially linking lymphocyte rolling with arrest. These cells had an effector phenotype because they lacked L-selectin and a higher proportion in diseased mice produced TNF and interleukin-2 compared with wild-type littermates. Lastly, CD4+ but not CD8+ T cells conferred ileitis to RAG−/− recipients and deficiency of one or both alleles of the CD44 gene resulted in attenuation of the severity of ileitis in TNFΔARE mice. Conclusions Our findings support an important role of CD44 expressed by CD4+ and CD8+ for development of ileitis mediated by TNF overproduction.