B Cell Development and T-Dependent Antibody Response Are Regulated by p38γ and p38δ

Abstract

p38MAP kinase (MAPK) signal transduction pathways are important regulators of inflammation and the immune response; their involvement in immune cell development and function is still largely unknown. Here we analysed the role of the p38 MAPK isoforms p38γ and p38δ in B cell differentiation in bone marrow (BM) and spleen, using mice lacking p38γ and p38δ, or conditional knockout mice that lack both p38γ and p38δ specifically in the B cell compartment. We found that the B cell differentiation programme in the BM was not affected in p38γ/δ-deficient mice. Moreover, these mice had reduced numbers of peripheral B cells as well as altered marginal zone B cell differentiation in the spleen. Expression of co-stimulatory proteins and activation markers in p38γ/δ-deficient B cells are diminished in response to B cell receptor (BCR) and CD40 stimulation; p38γ and p38δ were necessary for B cell proliferation induced by BCR and CD40 but not by TLR4 signaling. Furthermore, p38γ/δ-null mice produced significantly lower antibody responses to T-dependent antigens. Our results identify unreported functions for p38γ and p38δ in B cells and in the T-dependent humoral response; and show that the combined activity of these kinases is needed for peripheral B cell differentiation and function.

p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

“…p38α (called p38) has been a therapeutic target in CD treatment, but these treatments have not progressed beyond phase I/II clinical trials [ 2 ]. Interestingly, the less studied p38γ and p38δ (p38γ/p38δ) are essential in the immune response and regulate inflammatory molecule production [ 2 , 3 , 4 , 5 , 6 ]. Moreover, the importance of p38γ/p38δ in CRC development has been established in vitro and in an azoxymethane‐dextran sodium sulfate (AOM‐DSS)‐induced CAC model using p38γ/p38δ‐knockout mice [ 2 , 5 ].…”

The Dynamics of B Cell Aging in Health and Disease

“…Moreover, multiple studies investigating the APC function of B cells showed that B cell-derived cytokines contribute to T cell profile skewing, such as T helper (T H ) 1 or T H 2 (39,40). Most B cells, however, are activated via T cell-independent (TI) or T cell-dependent (TD) mechanisms (41). During T cellindependent (TI) B cell activation, antigens with repetitive epitopes, such as polysaccharides, bind to the BCR, resulting in BCR crosslinking (42).…”

ICAP‐1 loss impairs CD8+ thymocyte development and leads to reduced marginal zone B cells in mice

“…Proliferation indexes were obtained with FlowJo analysis software (BD Biosciences), showing the ratio of the total number of divisions between the number of cells that went into division. For B-cell proliferation assays, we followed the described method [63]. Briefly, CTV-labelled CD19 + B cells were cultured with goat anti-BCR (20 μg/mL; Jackson Immunoresearch, Ely, UK) plus recombinant mouse IL-4 (20 ng/mL Peprotech, London, UK), and after 96 h, cells were analyzed by flow cytometry and proliferation indexes obtained using FlowJo analysis software.…”

“…Briefly, CTV-labelled CD19 + B cells were cultured with goat anti-BCR (20 μg/mL; Jackson Immunoresearch, Ely, UK) plus recombinant mouse IL-4 (20 ng/mL Peprotech, London, UK), and after 96 h, cells were analyzed by flow cytometry and proliferation indexes obtained using FlowJo analysis software. For T-independent immunization assays, groups of four control and ICAP-1-null mice were immunized with TNP-Ficoll (Biosearch Technologies) as described in Ref, [63]. Peripheral blood samples were taken 24 h before immunization, and at days 7, 14, and 21 postimmunization.…”