The role of P110d in immunological memory

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PI3K are a family of enzymes that phosphorylate membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2) to generate PIP3. PIP3 is a second messenger that regulates the location and activity of a variety of effector proteins including kinases (such as PKB) and GEFs (e.g. Vav, PREx1). PI3K are activated by diverse stimuli and function by integrating these stimuli into changes in metabolism, apoptosis, proliferation, differentiation and more. Lymphocytes express multiple PI3K, however we have demonstrated a non-redundant role for p110d in the development of B lymphocytes. Furthermore, we have demonstrated the essential role for this PI3K in the humoral response to thymus-dependent and independent antigens. As there is clear evidence that P110d also plays an essential role in T cell activation this raised the question of whether the defect was intrinsic to B cells, T cells or both types of lymphocyte. To address this issue we generated a floxed allele of P110d (unpublished data). This mouse model will, for the first time, allow tissue specific and temporal control of P110d function.Key questions that remain to be answered include: What is the relative contribution of P110d activity in T cells versus B cells to the defects in humoral immunity? Is P110d required for the maintenance of established populations of antigen-specific memory and/or plasma cells? This is an important issue as nothing is known about this problem in terms of molecular signalling. Moreover, identifying the mechanisms that drive B cell differentiation into memory or plasma cells is important as it has implications for the design of vaccines and the problems of autoimmunity and cancers.

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