Retention of CXCR4 in the endoplasmic reticulum blocks dissemination of a T cell hybridoma

The dissemination of T cell hybridomas to multiple nonhematopoietic tissues is blocked by pertussis toxin, suggesting the involvement of a chemokine. To study whether this chemokine is SDF-1, we employed a strategy proposed p reviously for gene therapy of AIDS, whereby the SDF-1 receptor CXCR4 (also a coreceptor for HIV) is retained in the endoplasmic reticulum (ER) and fai ls to reach the cell surface. We transfected SDF-1, carrying an ER retentio n sequence, into a T cell hybridoma. This altered chemokine is retained in the ER, where it binds CXCR4 and prevents the latter protein from reaching the surface. These cells failed to migrate toward SDF-1 or to invade fibrob last monolayers, although they could still migrate toward thymus and activa tion-regulated chemokine (TARC) and invade TARC-treated monolayers. Further more, the ability of the transfected cells to disseminate to multiple organ s upon intravenous injection into mice was abolished. This dissemination re flects the in vivo migration patterns of activated and memory T cells into nonhematopoietic tissues, which is thus likely to depend on CXCR4. Attempts to block CXCR4 function as a therapy for AIDS may affect this migration wi th consequences for T cell function. Our results also suggest a decisive ro le for CXCR4 in the dissemination of hematopoietic malignancies expressing this receptor.