In Vivo–Activated Cd4 T Cells Upregulate Cxc Chemokine Receptor 5 and Reprogram Their Response to Lymphoid Chemokines

TLDR

Antigen‑activated CD4 T cells must migrate to B‑cell areas of lymphoid tissues to support antibody responses, and double‑negative T cells in MRL‑lpr mice normally accumulate within follicles. The study examined whether T cells could intrinsically acquire follicular‑homing capacity by analyzing CD4−CD8− double‑negative T cells from MRL‑lpr mice. Researchers mapped B‑lymphocyte chemoattractant (BLC) expression by in situ hybridization of secondary follicles and assessed chemokine receptor expression and responsiveness on isolated T cells. CXCR5 was up‑regulated on antigen‑specific CD4 T cells in vivo, conferring strong chemotaxis to BLC but reduced responsiveness to EBI‑1 ligand and SLC; adoptive transfer of CXCR5hi CD4 T cells failed to home to follicles, whereas transferred DN T cells migrated to follicle‑proximal regions, indicating that reprogramming of chemokine responsiveness is essential for T‑cell migration to the B‑cell compartment.

Abstract

Migration of antigen-activated CD4 T cells to B cell areas of lymphoid tissues is important for mounting T cell–dependent antibody responses. Here we show that CXC chemokine receptor (CXCR)5, the receptor for B lymphocyte chemoattractant (BLC), is upregulated on antigen-specific CD4 T cells in vivo when animals are immunized under conditions that promote T cell migration to follicles. In situ hybridization of secondary follicles for BLC showed high expression in mantle zones and low expression in germinal centers. When tested directly ex vivo, CXCR5hi T cells exhibited a vigorous chemotactic response to BLC. At the same time, the CXCR5hi cells showed reduced responsiveness to the T zone chemokines, Epstein-Barr virus–induced molecule 1 (EBI-1) ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC). After adoptive transfer, CXCR5hi CD4 T cells did not migrate to follicles, indicating that additional changes may occur after immunization that help direct T cells to follicles. To further explore whether T cells could acquire an intrinsic ability to migrate to follicles, CD4−CD8− double negative (DN) T cells from MRL-lpr mice were studied. These T cells normally accumulate within follicles of MRL-lpr mice. Upon transfer to wild-type recipients, DN T cells migrated to follicle proximal regions in all secondary lymphoid tissues. Taken together, our findings indicate that reprogramming of responsiveness to constitutively expressed lymphoid tissue chemokines plays an important role in T cell migration to the B cell compartment of lymphoid tissues.