Cell-surface transferrin receptor (CD71⁺) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71⁺ erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4⁺ T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71⁺VISTA⁺ erythroid cells produce significantly higher levels of TGF-β compared to CD71⁺VISTA⁻ erythroid cells and CD71⁺ erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71⁺VISTA⁺ erythroid cells—compared to CD71⁺VISTA⁻ and CD71⁺ erythroid cells from the VISTA KO mice—significantly exceed promotion of naïve CD4⁺ T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71⁺ erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71⁺ erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71⁺ erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71⁺ erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71⁺ erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71⁺ erythroid cells in the neonatal period and possibly beyond.

细胞表面转铁蛋白受体（CD71 ⁺）红细胞在具有免疫调节特性的新生儿中含量很高。在这里，我们表明，新生儿CD71 ⁺红细胞表达T细胞活化（VISTA）的V结构域免疫球蛋白（Ig）抑制子的水平很高，并且通过转化生长因子（TGF）-β的组成型产生，在促进中起关键作用将幼稚的CD4 ⁺ T细胞转化为调节性T细胞（Tregs）。有趣的是，我们发现，CD71 ⁺ VISTA ⁺红系相比CD71细胞产生显著较高水平的TGF-β ⁺ VISTA ^-红系细胞和CD71 ⁺来自VISTA基因敲除（KO）小鼠的类红细胞。其结果，CD71 ⁺ VISTA ⁺红细胞-相比CD71 ⁺ VISTA ^-和CD71 ⁺红细胞从VISTA KO小鼠-显著超过促进幼稚的CD4 ⁺通过TGF-β在体外T细胞分化为诱导的Tregs（的iTreg）。然而，CD71 ⁺红细胞的耗竭对体内Tregs的频率没有显着影响。令人惊讶的是，我们观察到剩余的和/或新生成的CD71 ⁺抗CD71抗体给药后的类红细胞表现出不同的基因表达谱，这由VISTA，TGF-β1，TGF-β2和程序性死亡配体1（PDL-1）的上调所证明，这可能是补偿性的维持Treg种群的机制。我们还观察到CD71 ⁺红系细胞的iTreg发育是通过抑制关键信号分子磷酸化蛋白激酶B（phospho-Akt）和雷帕霉素的磷酸化机制靶标（phospho-mTOR）介导的。最后，我们发现使用叉头盒P3（FOXP3）-白喉毒素受体（DTR）小鼠消除了Treg，导致CD71 ⁺体内的类红细胞。据我们所知，这些研究共同为新生儿CD71 ⁺红系细胞与Tregs之间的串扰提供了一种新颖的见解。我们的研究结果突显了CD71 ⁺红系细胞在新生儿期甚至更晚时期的生物学作用。