STAT-3 Activation by Differential Cytokines Is Critical for Human In Vivo–Generated Plasma Cell Survival and Ig Secretion

Abstract

Maturation and survival of plasma cells (PCs) depends on extrinsic factors provided in specialized niches. In addition, B lymphocyte differentiation into PCs requires the activation of the JAK–STAT-3 pathway. However, whether STAT-3 is needed only during the transition of B lymphocytes to PC, or it is also involved in the survival and function of PCs at different stages of maturation, has not been unequivocally clarified. This study analyzes the effect of IL-10, IL-21, and IL-6 on human in vivo–generated PCs isolated from secondary lymphoid organs, blood (circulating, recently Ag-induced PCs), and bone marrow. PCs from these different organs show specific profiles of receptors for, and responsiveness to, these cytokines required for their survival and sustained Ab secretion. However, IL-10, IL-21, and IL-6 commonly induce STAT-3 phosphorylation in the three PC subsets, and all of their effects are exerted strictly through the STAT-3 activation. The inhibition or nonactivation of this pathway in the three PC populations impairs not only the effect of STAT-3–activating cytokines, but also the action of other cytokines important at the PC level, including a proliferation-induced ligand, BAFF, insulin-like growth factor 1, vascular endothelial growth factor, and stromal cell–derived factor-1α. These results indicate that STAT-3 activation is critical for human PCs throughout their maturation.

Carp Il10 Has Anti-Inflammatory Activities on Phagocytes, Promotes Proliferation of Memory T Cells, and Regulates B Cell Differentiation and Antibody Secretion

“…IL-10-mediated increases in B cell survival, proliferation, terminal differentiation, and Ab secretion were reported in a multitude of studies in mammals (79)(80)(81). Therefore, in the last part of this study we focused on the regulatory activities of carp Il10 on B lymphocytes (IgM + ), in particular on the ability of Il10 to regulate B cell proliferation, differentiation, and Ab production.…”

Survival of Human Circulating Antigen-Induced Plasma Cells Is Supported by Plasma Cell–Niche Cytokines and T Follicular Helper Lymphocytes

“…Peripheral blood (PB) samples were obtained from healthy donors 6 d after receiving a conventional booster immunization against tetanusdiphtheria toxoids and acellular pertussis (Boostrix; GlaxoSmithKline Biologicals SA, Rixensart, Belgium) (23). BM specimens showing no abnormalities were collected from discarded BM aspirates obtained for diagnostic purposes.…”

“…It has been previously demonstrated that these PCs express functional CXCR4 (13,14,22), the receptor for CXCL12, a prerequisite for homing in BM PC niches (11,12). In addition, they have the capacity of responding to cytokines such as IL-6 and others present in the long-living PC niches (23). All of these features combined with its transient and temporary relation with serum Ab appearance have led to the belief that the blood Aginduced PC pool contains the precursors of long-living BM PCs specific for every Ag (11,12).…”

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

“…Beside its role in inducing IL-10 production 42,43 in B cells, IL-21 produced by human follicular helper T cells and CD4 Th17 cells is also critical for human plasmablast differentiation. [47][48][49][50] Elevated levels of IL-21 51 and IL-21-producing cells 52 have been found in human cGVHD and a deleterious role of IL-21 has been demonstrated in mouse models of cGVHD. 25,52 Accordingly, we found relatively high basal levels of phosphorylated STAT3 as well as increased circulating plasmablasts in cGVHD patients in our study.…”