CXCR4, but not CXCR3, drives CD8⁺ T‐cell entry into and migration through the murine bone marrow

Abstract

The BM serves as a blood‐forming organ, but also supports the maintenance and immune surveillance function of many T cells. Yet, in contrast to other organs, little is known about the molecular mechanisms that drive T‐cell migration to and localization inside the BM. As BM accumulates many CXCR3‐expressing memory CD8+ T cells, we tested the involvement of this chemokine receptor, but found that CXCR3 is not required for BM entry. In contrast, we could demonstrate that CXCR4, which is highly expressed on both naive and memory CD8+ T cells in BM, is critically important for homing of all CD8+ T‐cell subsets to the BM in mice. Upon entry into the BM parenchyma, both naïve and memory CD8+ T cells locate close to sinusoidal vessels. Intravital imaging experiments revealed that CD8 T cells are surprisingly immobile and we found that they interact with ICAM‐1+VCAM‐1+BP‐1+ perivascular stromal cells. These cells are the major source of CXCL12, but also express key survival factors and maintenance cytokines IL‐7 and IL‐15. We therefore conclude that CXCR4 is not only crucial for entry of CD8+ T cells into the BM, but also controls their subsequent localization toward BM niches that support their survival.

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“…In TME, naïve CD8 + T cells are differentiated into effector CD8+ T cells and further differentiated into cytotoxic and memory CD8+ T cells ( 103 ). CXCR4 is highly expressed in BM on both naive and memory CD8+ T cells where regulates homing to the BM in mice ( 104 ). CXCR4 in CD8+ T cells (T CXCR4 ) potentiates migration toward vascular-associated CXCL12-positive cells in the BM.…”

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“…CXCR4 is expressed in several cell types including HSPCs, where it plays an important role in the maintenance of stem cell interactions with components of the bone marrow [ 183 , 184 ]. CXCR4 signaling is also essential for B lymphopoiesis [ 185 , 186 ] and for T-cell migration to different organs, including CNS [ 187 , 188 , 189 , 190 , 191 ].…”