Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction.
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.
Rolf
Julia
J
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
Bell
Sarah E
SE
Kovesdi
Dorottya
D
Janas
Michelle L
ML
Soond
Dalya R
DR
Webb
Louise M C
LM
Santinelli
Sara
S
Saunders
Ted
T
Hebeis
Barbara
B
Killeen
Nigel
N
Okkenhaug
Klaus
K
Turner
Martin
M
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
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse