Extrathymic Hemopoietic Progenitors Committed to T Cell Differentiation in the Adult Mouse

Abstract

The role of the thymus in T cell commitment of hemopoietic precursor is yet controversial. We previously identified a major T cell progenitor activity in precursor cells isolated from bone marrow-derived spleen colonies. In this study, we characterize the properties of these pre-T cells. We demonstrate that they have unique phenotype and can be generated in a total absence of any thymic influence. Indeed, even when studied at the single-cell level, extrathymic T cell-committed precursors express T cell-specific genes. Moreover, these cells are not committed to a particular T cell differentiation pathway because they can generate both extrathymic CD8αα+ intraepithelial lymphocytes and thymus-derived conventional thymocytes. We also compared these pre-T cells with fully T cell-committed thymic progenitors. When tested in vitro or by direct intrathymic transfer, these cells have a low clonogenic activity. However, after i.v. transfer, thymus repopulation is efficient and these precursors generate very high numbers of peripheral T cells. These results suggest the existence of extra steps of pre-T cell maturation that improve thymus reconstitution capacity and that can be delivered even after full T cell commitment. Consequently, our studies identify a source of extrathymic progenitors that will be helpful in defining the role of the thymus in the earliest steps of T cell differentiation.

Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

“…However, this long-held view of exclusive T cell positive selection on radio-resistant thymic cells is under revision based on more recent studies suggesting that positive selection can occur on BM derived cells (10,(19)(20)(21), including fibroblasts or other MHC class II expressing cells in the thymic microenvironment (22)(23)(24). T cell development has also been shown to occur by extrathymic pathways (25,26). In addition, ''loose'' positive selection on MHC-disparate thymic epithelium may still allow a proportion of T cells to interact with APC in the periphery (27).…”

Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment

“…6A). Splenic pre-T cells were detected in nude mice (14,15) and are present before ETP generation following BM transfer (L. Gautreau and S. Ezine, unpublished observations) (16). Thus, they can be considered the first step toward commitment to the T cell pathway.…”

“…Meanwhile, progenitors with restricted T-lineage potential have been described in the gut (10,11), the BM (12), and the spleen (13)(14)(15). In fact, Lin 2 Thy1.2 + CD25 + IL7Ra + T cell precursors (pre-T cells) are naturally present in murine spleen (14,15) and are also found in the spleen after BM transplantation (13).…”

“…In fact, Lin 2 Thy1.2 + CD25 + IL7Ra + T cell precursors (pre-T cells) are naturally present in murine spleen (14,15) and are also found in the spleen after BM transplantation (13). These pre-T cells arise before the generation of early thymic progenitors (ETPs) (L. Gautreau and S. Ezine, unpublished observations) (16) and accumulate in the spleen after thymectomy (15), representing the first stage of an early T cell pathway.…”

Making T cells functional: a new solution for the athymic BMT recipients

“…They found that mice with impaired thymic function after BMT produced fully functional T cells, demonstrating that mesenteric lymph nodes (MLNs) can support T cell development and reconstitution in the absence of thymic function ( Figure 1B). Although the spleen, peripheral lymph nodes (PLNs), and BM support early lineage-negative or double positive (DP) cell progenitors after BMT [6] , the development of extrathymic T cells were only identified in gut-associated tissues, such as MLNs, Peyer's patches, intraepithelial sites, and lamina propria. By flow cytometry analysis, the MLN DP cells expressing cell-surface markers were at levels equivalent to thymic DP cells.…”