Missing-In-Metastasis / Metastasis Suppressor 1 modulates B cell receptor signaling, B cell metabolic potential and T cell-independent immune responses.

Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cells, activated by cognate antigens via B cell receptors (BCR) or pathogen-associated molecules through pattern-recognition receptors, such as TLRs, initiate signaling cascades leading to transcriptional and metabolic changes that ultimately transform B cells into efficient producers of antibodies. BCR signaling is also critical for normal development, as well as survival, of B cells, and critical for survival of different types of lymphomas. A number of steps initiated downstream of BCR rely on coordinated action of actin cytoskeleton, which is in turn dependent on concerted action of multiple actin-regulatory proteins, some of them exclusive to B cells. In our study we dissect the role of Missing-In-Metastasis, or Metastasis suppressor 1 (MIM, or MTSS1), a membrane- and actin cytoskeleton-associated I-BAR domain protein, in the regulation of B cell-mediated immunity. Differential expression of MIM has been associated with variety of cancers, whereas loss of MIM was found to lead to development of B cell lymphomas in adult mice, suggesting important functions in B cells. We take advantage of MIM knockout mouse strain and show normal B cell development and composition of B cell compartments in the periphery. However, we found that MIM-deficient B cells are defected in BCR signaling in response to surface-bound antigen and have higher metabolic activity after activation with LPS or CpG. In vivo MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides first comprehensive characterization of MIM in B cells and highlights its modulatory role for B cell-mediated immunity.