From the bone marrow to the periphery: Migratory pathways of T cells

T cells derive from progenitors that reside in the bone marrow (BM) and upon entering the circulation and migrating to the thymus, commit to T cells. Within the thymus, the T cell repertoire is screened and selected by positive and negative mechanisms followed by the release of mature naive T cells into the bloodstream. Naive T cells migrate then to secondary lymphoid organs (SLO) searching for cognate antigens. Once activated, they differentiate into short-lived effector cells, and upon antigen clearance some of them remain in the body as long-lived memory T cells. The goal of this thesis is to better understand the migratory mechanisms involved in different steps throughout the life of the T cell.; We isolate a novel common lymphoid progenitor population in the BM, CLP-2, which efficiently homes to the thymus where it gives rise to mature T cells. The homing comprises a unique multi-step adhesion cascade involving P-selectin/PSGL-1 interactions, CCL25-CCR9 signaling, alpha4beta1/VCAM-1 and alphaLbeta2/ICAM-1 interactions.; We also demonstrate that circulating immature dendritic cells (DCs) ex vivo loaded with antigenic peptide are recruited to the thymic medulla via P-selectin, G-protein coupled receptor-mediated signaling and alpha4beta1/VCAM-1 interactions and once there, they induce clonal deletion of TCR-specific thymocytes. This suggests an overlooked contribution of bloodborne DCs to the establishment and maintenance of central tolerance.; Following positive and negative selection, mature thymocytes exit the thymus and enter the bloodstream. We find that in mice deficient for the main lymphocyte-expressed receptor for sphingosine-1-phosphate (S1P1), T cells are retained in the thymus and do not leave SLO and BM after adoptive transfer into wild-type recipients. Furthermore, S1P1-/- T cells are defective in short-term homing to peripheral lymph nodes (PLNs). Therefore, S1P1 does not only control resident lymphocyte numbers in SLO at the level of lymphocyte egress, but also at the entry level by facilitating integrin-activation during homing.; Central memory T (TCM) cells, defined as L-selectin +CCR7+, recirculate mainly through SLO, including PLNs. Using homing and intravital microscopy experiments we show that TCM cells, unlike naive T cells, can home to PLNs in both a CCR7-dependent and -independent manner, which involves the CXCL12-CXCR4 pathway. Together, these data distinguish naive from TCM cells, whereby only the latter display greater migratory flexibility during homing to PLNs.