title: Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction.
abstract: The generation of high-affinity Abs is essential for immunity and requires collaboration between B and T cells within germinal centers (GCs). By using novel mouse models with a conditional deletion of the p110δ catalytic subunit of the PI3K pathway, we established that p110δ is required in T cells, but not in B cells, for the GC reaction. We found the formation of T follicular helper (T(FH)) cells to be critically dependent on p110δ in T cells. Furthermore, by deleting phosphatase and tensin homolog deleted on chromosome 10, which opposes p110δ in activated T cells, we found a positive correlation between increased numbers of T(FH) cells and GC B cells. These results are consistent with the hypothesis that T cell help is the limiting factor in the GC reaction. P110δ was not required for the expression of B cell lymphoma 6, the downregulation of CCR7, or T cell entry into primary follicles. Instead, p110δ was the critical catalytic subunit for ICOS downstream signaling and the production of key T(FH) cytokines and effector molecules. Our findings support a model in which the magnitude of the GC reaction is controlled by the activity of the PI3K pathway in T(FH) cells.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Rolf
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bell
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kovesdi
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Janas
authors.forename: Dalya R
authors.initials: DR
authors.lastname: Soond
authors.forename: Louise M C
authors.initials: LM
authors.lastname: Webb
authors.forename: Sara
authors.initials: S
authors.lastname: Santinelli
authors.forename: Ted
authors.initials: T
authors.lastname: Saunders
authors.forename: Barbara
authors.initials: B
authors.lastname: Hebeis
authors.forename: Nigel
authors.initials: N
authors.lastname: Killeen
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D002469:Cell Separation; D058534:Class I Phosphatidylinositol 3-Kinases; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018858:Germinal Center / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology* / Q000276:immunology
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse