Human T Lymphotropic Virus Type 1 Increases T Lymphocyte Migration by Recruiting the Cytoskeleton Organizer CRMP2

Abstract

Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1–induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69+ cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1–infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation.

Insight into the role of CRMP2 (collapsin response mediator protein 2) in T lymphocyte migration

“…25 In the context of HTLV-1 infection, the levels of full-length CRMP2 were always higher (compared with the short version) in infected compared with uninfected T cell clones. 37 Importantly, this correlated with the higher migratory rate of infected T cell clones. In addition, these cells displayed a more pronounced adhesion of full-length CRMP2 to the cytoskeletal components, tubulin and actin.…”

“…Comparative genomic analyses performed on CD69 + cells selected from HD and HTLV-1 infected patients suffering from TSP/HAM indicated that a number of genes involved in signaling pathways, downstream of chemokine receptors and cell migration, were specifically present in patients. 37 Patient cells exhibited a distinct profile, with 22 genes uniquely expressed and 10 others with a $ 3-fold increased expression. Several are involved in G protein and PI3K signaling.…”

“…[42][43][44] CRMP2 hyperphosphorylation could be involved in the enhanced migratory rate displayed by HTLV-1-infected T lymphocytes, as suggested by accumulation of the CRMP2-(pSer522), CRMP2-(pThr509/514) and CRMP2-(pTyr479) forms. 37 The reason for such an alteration remains unknown. Transfection of T lymphocytes to induce expression of the multifunctional viral protein, Tax, did not significantly modify the CRMP2 phosphorylation status.…”

“…37 CRMP2 is expressed in full-length and short processed forms, resulting from cleavage of the C-terminus by the calcium dependent protease, calpain. 47 Multiple putative phosphorylation sites are located on the C-terminus.…”

Transmission intercellulaire de HTLV-1

“…L'engagement de CADM-1 permet le recrutement de TIAM (T lymphoma invasion and metastasis), un facteur d'échange pour la GTPase Rac, l'activation de Rac et la formation de lamellipodes [25]. Gem et la fascine colocalisent avec l'actine [22,23], mais pas avec Tax, alors que CRMP-2 colocalise avec les microtubules et partiellement avec Tax au niveau des contacts cellule-cellule [26]. CRMP-2 permet l'assemblage des microtubules lorsqu'elle est phosphorylée par ROCK-II (Rho-associated, coiled-coil containing protein kinase 2), une kinase activée par la GTPase Rho, ce qui pourrait contrôler la polarisation du MTOC.…”