Yolanda R. Carrasco
Group Leader
Research summary
The B lymphocyte immune response leads to the production of antibodies that will neutralize and eliminate the pathogen, and of memory B cells that confer long-term immunity. Continuous adjustments in B lymphocyte behavior (cell motility, cell-to-cell interactions, immune synapse) are required for the success of the humoral immune response. This greatly depends on the cytoskeleton remodeling and mechanical properties of B lymphocytes.
Publications
Merino-Cortes SV, Gardeta SR, Roman-Garcia S, Martínez-Riaño A, Pineau J, Liebana R, Merida I, Lennon-Dumenil AM, Pierobon P, Husson J, Alarcon B, Carrasco YR. Diacylglycerol kinase ζ promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse. Science Signaling, 2020; 13, eaaw8214; doi: 10.1126/scisignal.aww8214. https://bit.ly/2VLsPTV
Carrasco YR Molecular cues involved in the regulation of B cell dynamics: assistants of antigen hunting. Journal of Leukocyte Biology, 2020; 15 Apr; doi: 10.1002/JLB.1MR0220-276R
Barrio L, Roman-Garcia S, Diaz-Mora E, Risco A, Jimenez-Saiz R, Carrasco YR, Cuenda A. B cell development and T-dependent antibody response are regulated by p38g and p38d Frontiers in Cell and Developmental Biology, 2020; 8 (189): 1-15; doi: 10.3389/fcell.2020.00189.
Sarapulov AV, Petrov P, Hernández-Pérez S, Sustar V, Kuokkanen E, Cords L, Samuel RVM, Vainio M, Fritzsche M, Carrasco YR, Mattila PK. Missing-in-Metastasis/Metastasis Suppressor 1 regulates B cell receptor signaling, B cell metabolic potential, and T cell-independent immune responses. Frontiers in Immunology, 2020; 11 (599): 1-20; doi: 10.3389/fimmu.2020.00599
Roman-Garcia S, Merino-Cortes SV, Gardeta SR, de Bruijn MJW, Hendriks RW, Carrasco YR. Distinct roles for Bruton’s tyrosine kinase in B cell immune synapse formation. Frontiers in Immunology, 2018; 9: 1-16; doi: 10.3389/fimmu.2018.02027
Martinez-Muñoz L, Rodriguez-Frade JM, Barroso R, Sorzano COS, Torreño-Piña JA, Santiago CA, Manzo C, Lucas P, Garcia-Cuesta EM, Gutierrez E, Barrio L, Vargas J, Cascio G, Carrasco YR, Sanchez-Madrid F, Garcia-Parajo MF, Mellado M. Separating actin-dependent chemokine receptor nanoclustering from dimerization indicates a role for clustering in CXCR4 signaling and function. Molecular Cell, 2018; 70 (1): 106-119. doi: 10.1016/j.molcel.2018.02.034
B lymphocytes patrol our body seeking for foreign pathogen-derived antigens. Recognition of antigen activates the B cell immune response, which leads in the end to the production of highly specific antibodies that will neutralize and eliminate the pathogen, and of memory B cells that confer long-term immunity. The complexity of the B cell response involved changes in lymphocyte behavior, switching from highly motile states to stable cell-to-cell interactions (immune synapse). Continuous adjustments of the cell mechanical properties (flexibility, stiffness) and cell polarity (MTOC and organelle distribution) are essential for such lymphocyte dynamics, and depend greatly on the remodeling of the cell cytoskeleton. Gene mutations or functional alterations in proteins related with these events are frequent in B cell pathologies (immunodeficiency, lymphomas), stressing their relevance for B cell function.
Our research focuses on the mechanisms that govern B lymphocyte dynamics, and how their dysfunction leads to or associates with B cell pathologies, in particular with B cell-lymphomas. We pursue to enrich the knowledge on those mechanisms and use it for therapeutic targeting. We recently revealed essential new functions of two proteins, Bruton’s tyrosine kinase (Btk) and the ζ isoform of Diacylglicerol kinases (DGKζ), both of interest for the clinic as therapeutic targets. Btk has a key role in the signaling of the B cell receptor for antigen and clinical trials with kinase inhibitors are on-going for B cell-lymphoma treatment. We found that Btk promotes the cell-cytoskeleton and adhesion-site remodeling needed for immune synapse formation mainly through its shuttling/scaffold activity. Impairment of that leads to B cell activation defects equivalent to those due to Btk kinase inhibition (Figure 1). Related with DGK ζ, known for diminishing antigen receptor signaling through DAG consumption, our findings showed that it also stimulates the B cell immune response. DGK ζ facilitates antigen extraction at the immune synapse by promoting actin-cytoskeleton remodeling and mechanical forces. B cell ability of antigen extraction is essential for antigen presentation to CD4 T cells and the germinal center response. Both events are reduced for DGK ζ-deficient B cells compared to wild type (Figure 2).
