Surface CD69-Negative CD4 and CD8 Bone Marrow-Resident Human Memory T Cells

Across tissues, tissue-resident memory T cells have been defined as cells that express CD69 on their cell surface but not sphingosine-1-phosphate receptor 1 (S1PR1), the receptor for the tissue-egress signal sphingosine-1-phosphate (S1P). It is less clear whether CD69-negative memory T cells are also tissue-resident. Here, we compare transcriptomes and T cell receptor repertoires of individual CD4 and CD8 memory T cells from paired blood and bone marrow samples from three human donors. CD69^- memory T cells of blood and bone marrow share transcriptionally defined clusters, characterized by signature genes and reflecting their imprinting during original activation. However, cells of related clusters from blood and bone marrow have different TCR repertoires, evidence that they represent distinct compartments of memory and indicating that the CD69^- memory T cells are residents of the bone marrow. Interestingly, the surface CD69^- memory T cells of bone marrow do transcribe the CD69 gene and express S1PR1, suggesting that they are blindfolded to the perception of the egress signal sphingosine-1-phosphate by dimerization and internalization of CD69 and S1PR1, maintaining them in the bone marrow.