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Abstract
The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-subfamily of small guanosine-5’-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (Rras −/−). An examination of the lymphoid organs of Rras −/− mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of Rras −/− mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from Rras −/− mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in Rras −/− T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, Rras −/− T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with Rras −/− T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response.
Highlights
R-Ras is a member of the RAS superfamily of small guanosine-5’-triphosphate (GTP)-binding proteins with approximately 56% amino-acid sequence homology to Ras oncogenes
Via an inside-out signaling mechanism, receptor activation enhances the affinity and avidity of both lymphocyte function-associated (LFA)-1/αLβ2 and very late antigen (VLA)-4/α4β1 integrins toward intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM), respectively
To elucidate the role of R-Ras in the developing lymphoid organs, thymus, spleen, and Peripheral lymph nodes (PLNs) were isolated from 6- to 8-week-old Rras+/+ and Rras−/− mice
Summary
R-Ras is a member of the RAS superfamily of small guanosine-5’-triphosphate (GTP)-binding proteins with approximately 56% amino-acid sequence homology to Ras oncogenes. R-Ras knockout mice develop normally without gross morphologic aberrations [17, 18]; they display greater angiogenic responses after arterial injury or tumor induction [17]. The signaling events that control firm adhesion have been studied extensively These involve the activation of the chemokine receptors CXCR4 and CCR7 on T cells by CXCL12 and CCL21, respectively [reviewed in [22]]. Via an inside-out signaling mechanism, receptor activation enhances the affinity and avidity of both lymphocyte function-associated (LFA)-1/αLβ2 and very late antigen (VLA)-4/α4β1 integrins toward intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM), respectively. These phenotypes are correlated with functional defects in proliferation, migration, and activation of R-Ras knockout T cells
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