Bone Marrow-Derived IL-13Rα1–Positive Thymic Progenitors Are Restricted to the Myeloid Lineage

Abstract

The earliest thymic progenitors (ETPs) were recently shown to give rise to both lymphoid and myeloid cells. While the majority of ETPs are derived from IL-7Rα-positive cells and give rise exclusively to T cells, the origin of the myeloid cells remains undefined. Herein, we show both in vitro and in vivo that IL-13Rα1+ ETPs yield myeloid cells with no potential for maturation into T cells while IL-13Rα1− ETPs lack myeloid potential. Moreover, transfer of lineage-negative IL-13Rα1+ bone marrow stem cells into IL-13Rα1-deficient mice reconstituted thymic IL-13Rα1+ myeloid ETPs. Myeloid cells or macrophages in the thymus are regarded as phagocytic cells whose function is to clear apoptotic debris generated during T cell development. However, the myeloid cells derived from IL-13Rα1+ ETPs were found to perform antigen presenting functions. Thus, IL-13Rα1 defines a new class of myeloid restricted ETPs yielding Ag presenting cells that could contribute to development of T cells and the control of immunity and autoimmunity.

IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

“…C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). IL-13Rα1 +/+ -GFP and IL-13Rα1 −/− C57BL/6 mice were previously described (9). Only female mice were used throughout the study.…”

“…For instance, we have previously reported that the unipotent attribute of an ETP subset identified in the thymus is tied to expression of the IL-13Rα1 chain (9), which is known to associate with IL-4Rα to form a functional heteroreceptor (HR) through which both IL-4 and IL-13 can signal (11–13). This HR-positive ETP subset (HR + ETP) is restricted to the myeloid lineage and gives rise to CD11b + cells both in vitro when cultured on stromal cells and in vivo when intra-thymically injected into HR-deficient (HR −/− ) mice (9). However, HR + ETPs do not to give rise to T cells either in vitro or in vivo upon intrathymic transfer (9).…”

“…This HR-positive ETP subset (HR + ETP) is restricted to the myeloid lineage and gives rise to CD11b + cells both in vitro when cultured on stromal cells and in vivo when intra-thymically injected into HR-deficient (HR −/− ) mice (9). However, HR + ETPs do not to give rise to T cells either in vitro or in vivo upon intrathymic transfer (9). These observations point to a link between the HR and restriction of commitment to the myeloid lineage as the HR offers a responsive element to the thymic environment that could be triggered by both IL-4 and IL-13 cytokines.…”

Neonatal Basophils Stifle the Function of Early-Life Dendritic Cells To Curtail Th1 Immunity in Newborn Mice

“…DO11.10/Rag2 −/− transgenic mice (H-2 d ) expressing OVA-specific TCR have been previously described (18). IL-13Rα1-deficient mice in which IL-13Rα1 gene expression was disrupted by deletion of exon 7, 8, and 9 were generated in our lab and have been previously described (17). IL-13Rα1 −/− DO11.10/Rag2 −/− mice have been generated by crossing IL-13Rα1 −/− Balb/c mice with DO11.10/Rag2 −/− mice.…”

“…How the function of neonatal DCs and their IL-12 are constrained, resulting in poor neonatal immunity, remains obscure. Because gene disruption of IL-13Rα1 preserves the conventional IL-4R but alters HR expression, we opted to utilize IL-13Rα1-deficient mice (17) to elucidate the physiological mechanism underlying IL-12 cytokine malfunction associated with neonatal DCs. Herein, it is shown that IL-13Rα1-deficient newborn mice dampen Th2 cells yet gain the ability to develop both primary and secondary Th1 immunity.…”