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

Abstract

<jats:title>Abstract</jats:title><jats:p>Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCR), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM<jats:sup>−/−</jats:sup> B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG. <jats:italic>In vivo</jats:italic>, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes which may also contribute to the poorly understood functions of MIM in cancer.</jats:p>

Loss of Rab8a in B cells leads to increased antibody responses and class-switch recombination

“…2D) and lymph nodes (Fig. S2A) and analysed the different immune cell populations as previously described ( Sarapulov et al ., 2020). To fully match the gating of the B cell (CD19+) populations, CD19-Cre controls were used here, instead of the littermate WT flox controls (see Fig.…”

“…Immunophenotyping Immunophenotyping was done as previously described (Sarapulov et al, 2020). Bone marrow cells were isolated by flushing the buffer through mouse femoral and tibial bones, and splenocytes were isolated by mashing the spleen.…”

“…Intracellular Ca 2+ Flux Splenic B cells were resuspended at a concentration of 5 × 106 cell/ml in RPMI supplemented with 20 mM HEPES and 2.5% FCS and loaded with 1 µM Fluo-4 (Thermo Fisher, #F14201) and 3 µM Fura Red (Thermo Fisher, #F3021) for 45 min (+37 °C, 5% CO 2 ) with occasional mixing (Sarapulov et al, 2020). After washing with cRPMI, cells were resuspended at 2.5 × 106 cells/ml in PBS supplemented with 20 mM HEPES, 5 mM glucose, 0.025% BSA, 1 mM CaCl 2 , 0.25 mM sulfinpyrazone (Sigma-Aldrich, #S9509), and 2.5% FCS.…”

Not all roads lead to the immune system: The Genetic Basis of Multiple Sclerosis Severity Implicates Central Nervous System and Mitochondrial Involvement

“…The variants we describe here are intronic to, or near to these genes, and are likely to be tagging rather than causal. However, together with IMMP2L, we describe three variants associated with mitochondrial function, where mitochondrial dysfunction is a recognised pathophysiological hallmark of CNS injury in MS. 48,49 Whilst MTSS1 has been reported to associate with mitochondrial function, it has primarily been described in the context of B-cell mediated immunity, 50 and various CNS pathologies. 51,52 Most relevant perhaps to MS outcomes, is the association between MTSS1, cortical volume, and Purkinje cell dendritic arborization.…”

“…Whilst MTSS1 has been reported to associate with mitochondrial function, it has primarily been described in the context of B-cell mediated immunity, 50 and various CNS pathologies. 51,52 Most relevant perhaps to MS outcomes, is the association between MTSS1 , cortical volume, and Purkinje cell dendritic arborization.…”