Author(s): Namita Saran, Jens Pommerencke, Katrin Witzlau, Malte Regelin, Andreas Krueger *
T cell development depends on continuous recruitment of progenitor cells from bone marrow (BM) to the thymus via peripheral blood . Thus, in order to qualify as physiological T cell precursors, cells a) must have T lineage potential; b) must be released into circulation; and c) must have the capacity to enter the thymus. Multiple populations have been described to fulfill all three criteria and some molecular cues required for progenitor entry into the thymus have been identified.
Using reductive isolation it has been demonstrated that all T cell precursors are confined to a heterogeneous population expressing CD135 (Flt3) and CD27 , . However, it remains unclear which subsets contribute to intrathymic T cell development. The CD135+ CD27+ population contains cells expressing high levels of CD117 (c-kit), that comprise various subsets of partially overlapping multipotent progenitors (MPP) that can be referred to as lymphoid-primed MPP (LMPP), early lymphoid progenitors (ELP) or L-selectin positive progenitors (LSP) , , . These cells can give rise to both lymphoid and myeloid progeny, which is consistent with the notion that early T lineage progenitors retain myeloid potential inside the thymus even after losing B lineage potential , . In addition, common lymphoid progenitors, characterized by expression of CD127 (IL-7R[alpha]) and intermediate expression of CD117 are part of the CD135+ CD27+ population. These cells are lymphoid-restricted in vivo . A third subset within the CD135+ CD27+ population in BM expresses CD90 (Thy-1) in addition to low levels of CD117 and CD127. These cells may constitute direct precursors to circulating T lineage progenitors (CTP), which were identified in peripheral blood and are largely T lineage restricted in vivo . Using lineage fate mapping based on the history of CD127 expression, which is indicative of lymphoid restriction, it has recently been suggested that the majority of early intrathymic precursors are derived from extrathymic cells that are already committed to the lymphoid lineage . These data remain yet to be reconciled with the proposed contribution of T lineage precursors to intrathymic myeloid cells . We have previously shown that multiple phenotypically distinct CD135+ CD27+ progenitor subsets can contribute to T lineage differentiation in the thymus . These subsets include cells expressing high levels of CD117, or are positive for CD127 or CD90. In addition, we observed low levels of transient T cell development even after depletion of all three subsets, suggesting that additional T lineage precursors with a CD117-/low CD127- CD90- phenotype exist . These cells expressed low levels of the chemokine receptors CCR7 and CCR9, which together are required for precursor entry into the thymus, as well as PSGL-1, the ligand for P-selectin, which also contributes to thymus seeding , , , .
Here we characterized lineage potential and T lineage differentiation of putative CD117-/low CD127- CD90- T cell precursors in vitro and in vivo in order to test the hypothesis that...