A Profound Deficiency in Thymic Progenitor Cells in Mice Lacking Jak3

Abstract

Humans and mice with genetic deficiencies that lead to loss of signaling through common γ-chain (γc)-containing cytokine receptors have severe defects in B and T lymphocytes. In humans, these deficiencies lead to a complete absence of T cells, whereas in mice, small thymuses give rise to normal numbers of peripheral T cells. We have examined the first wave of developing T cells in Jak3−/−, IL-7−/−, and IL-7Rα−/− fetal mice, and have found a near absence of thymic progenitor cells. This deficiency is highlighted by the complete inability of Jak3−/− progenitor cells to reconstitute T cell development in the presence of competing wild-type cells. These data clearly demonstrate a strong common basis for the T cell deficiencies in mice and humans lacking γc/Jak3 signaling pathways.

Regulation of Thymus Size by Competition for Stromal Niches among Early T Cell Progenitors

“…4). More specifically, these data, which are consistent with the findings of others (32,35,36), suggest that of all the DN stages, DN3 cells appear to most strongly factor into the equation, with a possible secondary contribution by DN2. DN1 cells appear unlikely to be involved, because IL-7R␣ Ϫ/Ϫ , RAG-2 Ϫ/Ϫ , SCID, and ␥ c Ϫ/Ϫ mice all have reduced numbers of DN1 cells (Table I, and Refs.…”

“…However, as mentioned above, both responsive and refractory strains exhibited a reduction in DN1 cell numbers (Table I, and Refs. 32,[35][36][37]. Thus, while new progenitor homing to the thymus is almost certainly controlled by competition for specific stromal niches (2), our data suggest that once inside the thymus, competition for intrathymic stromal niches acts independently to regulate the intrathymic expansion process.…”

“…DN1 cells appear unlikely to be involved, because IL-7R␣ Ϫ/Ϫ , RAG-2 Ϫ/Ϫ , SCID, and ␥ c Ϫ/Ϫ mice all have reduced numbers of DN1 cells (Table I, and Refs. 32,[35][36][37], but differ substantially in their abilities to be reconstituted by wildtype marrow (Fig. 1).…”

Gated Importation of Prothymocytes by Adult Mouse Thymus Is Coordinated with Their Periodic Mobilization from Bone Marrow

“…Given that IL-7R has been shown to activate integrin-mediated adhesion of early thymocytes (41), it is reasonable to speculate that IL-7 signaling may be involved in IMV gate closing. Alternatively, the effect of IL-7 may be indirect, if IL-7R Ϫ/Ϫ prothymocytes, like their Janus kinase 3 Ϫ/Ϫ counterparts (42), are present in abnormally low numbers in BM or fail to efficiently bind to the IMN niches.…”

Characterization and Analysis of the Proximal Janus Kinase 3 Promoter

“…IL-7 has been demonstrated to be essential for proper lymphoid survival and function in mice and humans (13)(14)(15)(16)(17)(18)(19). By contrast, IL-15 is essential for proper NK cell development, as is apparent in mice deficient in this cytokine receptor (20).…”