CXCR5-dependent entry of CD8 T cells into rhesus macaque B-cell follicles achieved through T-cell engineering

Victor I. Ayala, Claire Deleage, Matthew T. Trivett, Sumiti Jain, Lori V. Coren, Matthew W. Breed, Joshua A. Kramer, James A. Thomas, Jacob D. Estes, Jeffrey D. Lifson, David E. Ott

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Follicular helper CD4 T cells, TFH, residing in B-cell follicles within secondary lymphoid tissues, are readily infected by AIDS viruses and are a major source of persistent virus despite relative control of viral replication. This persistence is due at least in part to a relative exclusion of effective antiviral CD8 T cells from B-cell follicles. To determine whether CD8 T cells could be engineered to enter B-cell follicles, we genetically modified unselected CD8 T cells to express CXC chemokine receptor 5 (CXCR5), the chemokine receptor implicated in cellular entry into B-cell follicles. Engineered CD8 T cells expressing human CXCR5 (CD8hCXCR5) exhibited ligandspecific signaling and chemotaxis in vitro. Six infected rhesus macaques were infused with differentially fluorescent dye-labeled autologous CD8hCXCR5 and untransduced CD8 T cells and necropsied 48 h later. Flow cytometry of both spleen and lymph node samples revealed higher frequencies of CD8hCXCR5 than untransduced cells, consistent with preferential trafficking to B-cell follicle-containing tissues. Confocal fluorescence microscopy of thin-sectioned lymphoid tissues demonstrated strong preferential localization of CD8hCXCR5 T cells within B-cell follicles with only rare cells in extrafollicular locations. CD8hCXCR5 T cells were present throughout the follicles with some observed near infected TFH. In contrast, untransduced CD8 T cells were found in the extrafollicular T-cell zone. Our ability to direct localization of unselected CD8 T cells into B-cell follicles using CXCR5 expression provides a strategy to place highly effective virus-specific CD8 T cells into these AIDS virus sanctuaries and potentially suppress residual viral replication.

Original languageEnglish (US)
Article numbere02507-16
JournalJournal of virology
Volume91
Issue number11
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

  • B-cell follicles
  • CD8 T cells
  • CXCR5
  • T-cell homing

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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