Splenic Long-Lived Plasma Cells Promote the Development of Follicular Helper T Cells during Autoimmune Responses

Abstract

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.

Function and dysfunction of plasma cells in intestine

“…T cells, primed with DCs or LLPCs, but not with SLPCs, can provide CD40L signals to B cells. Consistent with this, only CD4+ T cells primed with DCs or LLPCs, but not those primed with SLPCs, helped cognate B cells to differentiate to ASCs [121]. Regarding the molecular mechanisms underlying the action of LLPCs, it can be suggested that their effect on TFH polarization might be related to their reduced capacity to prime CD4+ T cells and their reduced IL-2 signaling, which inhibit TFH differentiation by inducing STAT5-dependent expression of Blimp-1, a repressor of BCL-6 [122–124].…”

The Function of FK506-Binding Protein 13 in Protein Quality Control Protects Plasma Cells from Endoplasmic Reticulum Stress-Associated Apoptosis

“…Third, they evade immune complex-mediated cell death by downregulating the death receptor FcγRIIb ( 29 ). Finally, they promote the differentiation of follicular helper T cells, so forming a positive feedback loop that amplifies humoral immunity ( 6 ). Therefore, a strategy limiting the longevity of these cells would be beneficial in controlling diseases related to long-lived PCs and plasmacytoma cells.…”

“…However, when PCs reside in milieu providing survival niches for them, such as bone marrow (BM) and inflamed sites, they terminally differentiate into post-mitotic PCs attaining a life span of months or even decades ( 1 ). These long-lived PCs have been known to be crucial for long-lasting immunity in experimental animals and humans ( 2 – 6 ), but little is known about how they sustain viability for such a long period.…”

Aged Sanroque Mice Spontaneously Develop Sjögren's Syndrome-like Disease

“…Spleen and cervical lymph node (cLN) cells from 35–40-wk-old mice were analyzed by FACS, as previously described (20). The following mAbs and reagents were purchased from BD Biosciences (San Jose, CA, USA) or eBioscience (San Diego, CA, USA): anti-CD4-PerCP, anti-Bcl6-FITC, anti-CXCR5-biotin, streptavidin-allophycocyanin (APC), anti-CD44-APC-Cy7, anti-GL7-FITC, anti-Fas-PE, anti-B220-PerCP, and anti-CD138-APC.…”