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

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 p38 gamma and p38 delta in B cell differentiation in bone marrow (BM) and spleen, using mice lacking p38 gamma and p38 delta, or conditional knockout mice that lack both p38 gamma and p38 delta specifically in the B cell compartment. We found that the B cell differentiation programme in the BM was not affected in p38 gamma/delta-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 p38 gamma/delta-deficient B cells are diminished in response to B cell receptor (BCR) and CD40 stimulation; p38 gamma and p38 delta were necessary for B cell proliferation induced by BCR and CD40 but not by TLR4 signaling. Furthermore, p38 gamma/delta-null mice produced significantly lower antibody responses to T-dependent antigens. Our results identify unreported functions for p38 gamma and p38 delta 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.