Patients with a combined immunodeficiency characterized by normal numbers, but impaired function, of T and B cells had a homozygous p.Tyr20His mutation in transferrin receptor 1 (TfR1), encoded by TFRC. The mutation disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 surface expression. Iron citrate rescued the lymphocyte defects and transduction of wild type, but not mutant, TfR1 rescued impaired transferrin uptake in patient fibroblasts. TfrcY20H/Y20H mice recapitulated the patients’ immunologic defects. Despite the critical role of TfR1 in erythrocyte development and function, the patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares the patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.

Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult lowploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome. IntroductionMegakaryocytopoiesis is the process by which hematopoietic stem cells undergo lineage commitment to become megakaryocyte (MK) progenitors, which proliferate and generate immature MKs. These immature MKs then undergo successive rounds of endomitosis that give rise to unique highly polyploid cells. The process of polyploidization is associated with the increasing production of proteins necessary for platelet formation and function, 1 including membrane receptors such as CD41/61 and CD42, and platelet granule components such as VWF, platelet factor 4, and P-selectin. Polyploidization is also accompanied by progressive ultrastructural changes, particularly the formation of a complex demarcation membrane system (DMS), which, together with an accumulation of ␣ granules, characterizes fully mature MKs. These events set the stage for the production of proplatelets and the release of platelets by mature MKs. 2 Over the last decades, a mounting body of evidence has supported the existence of substantial biologic differences between fetal/neonatal and adult MKs. Several in vitro studies have shown that MK progenitors from fetuses and neonates proliferate at a much higher rate than adult progenitors. [3][4][5] Neonatal MKs, however, are significantly smaller and of lower ploidy (and produce fewer platelets) than MKs from adults. [6][7][8] Based on these characteristics, MKs from fetuses and neonates have been considered to be immature compared with adult MKs. 9 Whereas the cellular and m...

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