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BAFF and CD4+ T cells are major survival factors for long-lived splenic plasma cells in a B-cell-depletion context

Lan-Huong Thai, Simon Le Gallou, Ailsa Robbins, Etienne Crickx, Tatiana Fadeev, Zhicheng Zhou, Nicolas Cagnard, Jérôme Mégret, Christine Bole, Jean-Claude Weill, Claude-Agnès Reynaud and Matthieu Mahévas

Key points

  • Modification of the splenic microenvironment induced by B-cell depletion creates a dependence of plasma cells towards BAFF and CD4+ T cells.

  • Combining anti-CD20 and anti-BAFF reduce the number of splenic plasma-cells, opening therapeutic perspectives for antibody-mediated cytopenia.

Abstract

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow PCs engaged in an immune response. Multiplex-PCR at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone-marrow PCs. It suggested that, in addition to a process of selection, a maturation induced upon B-cell depletion drove PCs toward a long-lived program. We showed that BAFF and CD4+ T cells play a major role in PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell-intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B cell depletion might improve the response rate in autoimmune cytopenia.

  • Submitted June 19, 2017.
  • Accepted January 16, 2018.