Thymus antibody-secreting cells possess an interferon-responsive gene signature and are comprised of a CD154(CD40L) dependent plasmablast population.

Abstract

Abstract Antibody-secreting cells (ASCs) consist of short-lived plasmablasts and post-mitotic mature plasma cells. While the major function of these cells is the production of antibodies, ASCs have been shown to regulate hematopoiesis and as well as the immune response in a context dependent manner. For years, it has been known that ASCs accumulate in the thymus of individuals with autoimmune disorders such as myasthenia gravis. In these instances, thymus ASCs persist long-term and generate pathogenic autoantibodies. However, it remains unclear how these cells are produced and regulated in the thymus under healthy conditions. Understanding these basic concepts may provide clues as to the emergence of select autoimmune diseases. As such, we have investigated the mechanisms of generation and the transcriptional landscape of thymus ASCs and compared these features to their counterparts in the bone marrow and spleen. Examination of ASC numbers demonstrated an organ-specific sex bias which manifested as increased numbers in the female thymus relative to males. Flow cytometric analysis for the proliferation marker Ki-67 demonstrated the presence of Ki-67 +plasmablasts. The administration of CD154(CD40L) blocking antibodies led to significant reduction in Ki-67 +ASCs as well as Ki-67 +B cells in the thymus. As CD40 expression was nearly exclusive to thymus B cells, the effect of CD154(CD40L) blockade was most likely mediated on upstream B cells. Finally, single cell RNA-sequencing revealed that thymus ASCs possessed an interferon-responsive gene signature which was validated at the protein level. Overall, these data provide insights as to the generation and regulation of thymus ASCs which can be leveraged for future studies. This work was supported by the National Institute on Aging of the National Institutes of Health under Award Number R03AG071955.