CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

Area of Science:

• Immunology
• Virology
• Cellular Biology

Background:

• Persistent human immunodeficiency virus (HIV) infection is often harbored in B-cell follicles by infected follicular helper CD4 T cells (T_FH).
• Antiviral CD8 T cells are crucial for controlling viral replication but are largely excluded from B-cell follicles, creating viral sanctuaries.

Purpose of the Study:

• To investigate if genetically engineering CD8 T cells to express CXC chemokine receptor 5 (CXCR5) can direct them into B-cell follicles.
• To assess the feasibility of using engineered CD8 T cells to target persistent HIV reservoirs within lymphoid tissues.

Main Methods:

• CD8 T cells were genetically modified to express human CXCR5 (CD8^hCXCR5).
• In vitro assays confirmed ligand-specific signaling and chemotaxis of engineered cells.
• Rhesus macaques infected with HIV were infused with autologous CD8^hCXCR5 and untransduced CD8 T cells, followed by analysis of lymphoid tissues.

Main Results:

• Engineered CD8^hCXCR5 T cells demonstrated preferential trafficking to B-cell follicle-containing tissues (spleen and lymph nodes) compared to untransduced cells.
• Confocal microscopy confirmed strong localization of CD8^hCXCR5 T cells within B-cell follicles, with some cells near infected T_FH cells.
• Untransduced CD8 T cells were primarily found in extrafollicular T-cell zones.

Conclusions:

• Expression of CXCR5 effectively redirects CD8 T cells into B-cell follicles, overcoming their natural exclusion.
• This engineered approach provides a strategy to deliver antiviral CD8 T cells to HIV sanctuaries.
• Targeting these viral reservoirs with engineered T cells holds potential for suppressing residual HIV replication.