A low lymphocyte count puts immune‐compromised patients at risk of mortality. hIL‐7‐hyFc is a homodimeric interleukin‐7 (IL‐7), a potent T‐cell amplifier, fused to the hybridizing IgD/IgG4 immunoglobulin domain. We performed a randomized, double‐blind, placebo‐controlled, dose‐escalation, phase I study to assess the pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles of hIL‐7‐hyFc administered s.c. and i.m. to healthy volunteers. Thirty subjects randomly received hIL‐7‐hyFc or its matching placebo in an 8:2 ratio at 20, 60 μg/kg s.c., or 60 μg/kg i.m. The hIL‐7‐hyFc was slowly absorbed and its terminal half‐life was 63.26 hours after i.m. administration. The hIL‐7‐hyFc increased absolute lymphocyte count, mostly in T‐cells, which peaked 3 weeks after administration and then lasted for several additional weeks. The hIL‐7‐hyFc was well‐tolerated after a single s.c. and i.m. administration. Injection site reaction was the most common treatment‐emergent adverse event, which resolved spontaneously without treatment. The hIL‐7‐hyFc can be developed into a beneficial treatment option for patients with compromised T‐cell immunity. This trial was registered at http://www.clinicaltrials.gov as #NCT02860715.

Early growth response (Egr)-1 is a Cys2-His2-type zincfinger transcription factor. It has been shown to induce survival and proliferation of immature and mature B cells, respectively, but its role in the differentiation of B cells into plasma cells remains unclear. To examine the effects of Egr-1 deficiency on the activation of B cells, naive B cells from Egr1-/- mice and their wild-type (WT) littermates were activated to proliferate and differentiate, and then assayed by FACS. Proportions of cells undergoing proliferation and apoptosis did not differ between Egr1-/- and WT mice. However, Egr1-/- B cells gave rise to fewer plasma cells than WT B cells. Consistently, Egr1-/- mice produced significantly lower titer of antigen-specific IgG than their WT littermates upon immunization. Our results demonstrate that Egr-1 participates in the differentiation program of B cells into plasma cells, while it is dispensable for the proliferation and survival of mature B cells.

Long-lived plasma cells (LLPCs) develop under the help of follicular helper T (Tfh) cells and reside mainly in the bone marrow. However, these cells are unusually abundant in the spleen of several autoimmune models including K/BxNsf mice, yet their pathogenic impact remains unknown. To investigate a previously unappreciated role of splenic LLPCs, we sorted splenic plasma cells (PCs) from K/BxNsf and K/BxN mice, corresponding to LLPCs and conventional short-lived PCs, respectively, and compared their phenotypes and ability to prime and induce the differentiation of naive CD4+ T cells into effector cells in vitro and in vivo. We found that K/BxNsf PCs had lower levels of the Ag presentation machinery and costimulators than K/BxN PCs, and also a lower CD4+ T cell priming capacity. Autoantigen-pulsed K/BxNsf PCs selectively polarized cognate CD4+ T cells toward the expression of molecules necessary for Tfh development and function. As a result, the K/BxNsf PC-primed CD4+ T cells were more effective in stimulating B cells to produce autoantigen-specific IgGs than K/BxN PCs or even dendritic cells. Adoptive transfer of K/BxNsf PCs, but not K/BxN PCs, to K/BxN mice increased numbers of Tfh cells in draining lymph nodes. These results propose that abnormal accumulation of LLPCs in the spleen of autoimmune models drives the differentiation of autoantigen-primed CD4+ T cells to Tfh cells. This positive feedback loop between splenic LLPCs and Tfh cells may contribute to the persistence of humoral autoimmunity.

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