Background/Purpose: Since the description of age-associated B cells (ABC), there has been a growing interest in the role of these cells in autoimmunity. Evidence suggests that ABC are involved in antigen presentation, autoantibody production and demonstrates a particular response to Toll-like receptor stimulation^1,2. The study of lymphocyte metabolism in SLE has revealed that metabolic pathways are hyperactivated in lupus-prone mice compare to controls and that the treatment with metabolic inhibitors reverses these changes^3,4. In this study, we test the hypothesis that ABC cells show increased metabolic activity and the altered metabolism in ABCs is responsible for the promotion of Tfh cell differentiation.

Methods: ABC cells were identified by the definition of CD11c+/ CD11b+ in CD19+ B cells by flow cytometry analysis. For the metabolism study, ABCs were isolated from spleens of 10–12-month old lupus-prone mice, triple congenital sle1,2,3 (TC) and B6.lpr, and age-matched C57BL/6 controls, and metabolism (oxygen consumption (OCR) and extracellular acidification rate (ECAR)) was analyzed by the seahorse assay with XFp cell mito stress kit. Tfh differentiation was conducted by co-culture of naïve CD4+ T cells and isolated ABCs or follicular B cells (FO B) for 3 days. After the co-culture, Tfh cells were identified by CXCR5+/PD1+ CD4+, and activation of T cells were measured by the expression of CD44 on T cells by flow cytometry analysis. Under similar co-culture condition of ABC and Naïve CD4+ T cells, the effects of various agents, Metformin, Etomoxir and N-Acetyl cysteine on differentiation was assessed.

Results: We observed that ABCs have increased mitochondrial metabolism (but not glycolysis measured by ECAR) in lupus-prone mice compared to ABC from age-matched controls. No difference in metabolism was found in FO B cells between lupus mice and controls. After 72 hours of coculture condition naïve CD4 T cells with B cells, both FO B and ABCs induced T cell activation and proliferation equally, but there was a higher percentage of activated T cells differentiated into CXCR5+ PD1+ Tfh cells by ABCs compared to T cells with FO B. The differentiation and activation of T cells were suppressed by metformin treatment.

Conclusion: ABC cells show an increase in mitochondrial metabolism measured by OCR compared to controls. Coculture of ABCs with naïve CD4 T cells induced differentiation to T cells with makers of Tfh cells. Blocking of mitochondrial activation by metformin could suppress Tfh differentiation. This data suggests that this increase in metabolic activity might correspond with the inflammatory profile of ABCs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/metabolic-characteristics-of-age-related-b-cells-in-lupus-prone-mice-and-effects-on-follicular-helper-t-cells/