Opposing chemokine gradients control human thymocyte migration in situ

Abstract

The ordered migration of thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of thymocyte migration rely on mouse models, but we know relatively little about how human thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4 + CD8 + double-positive (DP) thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human thymocytes in both mouse and human thymic stroma and found that human thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP thymocytes in the cortex, whereas CCR7 promoted migration of mature human thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of thymocytes from the cortex to the medulla. These findings point to significant interspecies conservation in thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature thymocytes to the medulla, but also play an active role in retaining DP thymocytes in the cortex prior to positive selection.

Distinct phases in the positive selection of CD8+T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

“…High motility is a consistent feature of SP thymocytes in the medulla (6,25,34,35) and mature T cells in lymph nodes (36), implying that increased motility reflects long-lasting changes in the cellular machinery that controls migration, rather than a short-term response to a chemokine gradient. Consistent with this notion, gene-expression studies of pre-and postselection DP thymocytes revealed induction of numerous genes that may play a role in regulating cell adhesion, metabolism, and the cytoskeleton (37)(38)(39).…”

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

“…Other examples of chemokines acting as retention factors are known. Most notable is the case of CXCR4 in hematopoietic stem cells, which are kept within the bone marrow niche by the ligand CXCL12; a similar situation occurs in immature thymocytes retained in the thymic cortex by the CXCR4-CXCL12 axis (58). Another chemokine- receptor pair (CCL25-CCR9) was demonstrated to modulate colon cancer invasion and metastasis (59).…”

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

“…Furthermore, human and xenografted CD8 T cells show similar distribution of CD45RA + naive cells and CD45RO + memory cells, but CD4 CD45RO + memory T cells are present in a significantly higher proportion in the transplanted NSG mice (P = 0.009), which might point to ongoing homeostatic proliferation in the CD4 compartment. Analysis of the interaction between murine thymic stroma and human T cells showed that T cells are capable of migrating to the site where they are expected to reside, corresponding to their developmental stage in mouse thymus in response to murine Ccl25, Cxcl12, and Ccl21, all chemokines that attract T cells to the thymus (38) 40), where HLA-A2 transgenic NSG were compared with normal NSG after transplantation of HLA-A2…”