PIK3IP1 Promotes Extrafollicular Class Switching in T-Dependent Immune Responses

Abstract

PI3K plays multiple roles throughout the life of a B cell. As such, its signaling is tightly regulated. The importance of this is illustrated by the fact that both loss-and gain-of-function mutations in PI3K can cause immunodeficiency in humans. PIK3IP1, also known as TrIP, is a transmembrane protein that has been shown to inhibit PI3K in T cells. Results from the ImmGen Consortium indicate that PIK3IP1 expression fluctuates throughout B cell development in a manner inversely correlated with PI3K activity; however, its role in B cells is poorly understood. In this study, we define the consequences of B cell-specific deletion of PIK3IP1. B cell development, basal Ig levels, and T-independent responses were unaffected by loss of PIK3IP1. However, there was a significant delay in the production of IgG during T-dependent responses, and secondary responses were impaired. This is likely due to a role for PIK3IP1 in the extrafollicular response because germinal center formation and affinity maturation were normal, and PIK3IP1 is not appreciably expressed in germinal center B cells. Consistent with a role early in the response, PIK3IP1 was downregulated at late time points after B cell activation, in a manner dependent on PI3K. Increased activation of the PI3K pathway was observed in PIK3IP1-deficient B cells in response to engagement of both the BCR and CD40 or strong cross-linking of CD40 alone. Taken together, these observations suggest that PIK3IP1 promotes extrafollicular responses by limiting PI3K signaling during initial interactions between B and T cells.

BCR Affinity Influences T-B Interactions and B Cell Development in Secondary Lymphoid Organs

“…However, strong PI3K signaling also inhibits CSR (59,60). In T-dependent EF responses, antagonism of the PI3K signaling pathway via activity of PI3K interacting protein 1 (PIK3IP1) promotes CSR, which was recently demonstrated by Ottens and colleagues (61). Mice with CD19-cre mediated PIK3IP1 deletion show delayed production of IgG1 after immunization with NP conjugated to keyhole limpet hemocyanin (KLH), a T-dependent antigen.…”

Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells

“…In human activated PI3K-δ syndrome (APDS), caused by mutations in PIK3CD and PIK3R1, hyperactive mTOR is linked to defective class-switch recombination (CSR) and conventional memory formation and enhanced formation of EF (CD21 low T-bet + ) B cells and ASCs (17,82,83). Defective CSR was also observed in mouse models with conditional deletion of the PI3K inhibitor PIK3IP1 (84). We showed that in FAS-competent B cells, FAS engagement can modulate mTOR activation in vitro, and this modulation was abrogated in ALPS-FAS patients' B cells.…”

T‐bet‐expressing B cells contribute to the autoreactive plasma cell pool in Lyn‐/‐ mice

“…[16]. 1:1000, 1:4000, and 1:16 000 dilutions of serum and 1:10, 1:40, and 1:160 dilutions of culture supernatant were subjected to total IgM, IgG, IgG1, and IgG2c ELISA as described [16,47].…”