The understanding of TACI function over time. (A) The initial analysis of TACI-deficient mice (2001–2003) indicated that TACI inhibited B cell survival because both FO and MZ B cells were expanded. Subsequent studies determined that TACI deficiency increased BAFF, suggesting that abnormally high BAFF-R signaling caused the B cell expansion. The differentiation of MZ B cells from T2 B cells was mostly attributed to BCR and NOTCH2 receptors, with a BAFF-R component found at a later time. (B) Luff et al. (2026) show that TACI interacts with BAFF-R in response to BAFF and promotes T2 B cell differentiation into MZ B cells through a mechanism likely involving cooperation with BAFF-R as well as BCR and NOTCH2. (C) Luff et al. (2026) show that TACI stimulates T2 B cell differentiation into MZ B cells via a PI3K–AKT pathway, leading to KLF2-facilitated FOXO inactivation. By inhibiting the TSC1–TSC2 mTORC1 suppressor complex, the PI3K–AKT pathway also activates mTORC1, which further contributes to MZ B cell development in addition to enhancing MZ B cell metabolic fitness. Refer to the image caption for details. Panel A: A flowchart showing TACI inhibits MZ B cell survival. Elevated BAFF binds to BAFF-R on T2 B cells, but TACI deficiency impairs this process, leading to FO B cell expansion and impaired TI antibody response. Panel B: A flowchart showing TACI promotes MZ B cell development. BAFF binds to BAFF-R and TACI on T2 B cells, promoting both FO B cell and MZ B cell development and TI antibody response. Panel C: A detailed diagram of the TACI-PI3K-AKT signaling pathway. BAFF binds to TACI, activating PI3K and converting PIP2 to PIP3. This activates PDK1 and AKT, leading to metabolic signaling and MZ B cell development through phosphorylation of various proteins including FOXO1.

The understanding of TACI function over time. (A) The initial analysis of TACI-deficient mice (2001–2003) indicated that TACI inhibited B cell survival because both FO and MZ B cells were expanded. Subsequent studies determined that TACI deficiency increased BAFF, suggesting that abnormally high BAFF-R signaling caused the B cell expansion. The differentiation of MZ B cells from T2 B cells was mostly attributed to BCR and NOTCH2 receptors, with a BAFF-R component found at a later time. (B) Luff et al. (2026) show that TACI interacts with BAFF-R in response to BAFF and promotes T2 B cell differentiation into MZ B cells through a mechanism likely involving cooperation with BAFF-R as well as BCR and NOTCH2. (C) Luff et al. (2026) show that TACI stimulates T2 B cell differentiation into MZ B cells via a PI3K–AKT pathway, leading to KLF2-facilitated FOXO inactivation. By inhibiting the TSC1–TSC2 mTORC1 suppressor complex, the PI3K–AKT pathway also activates mTORC1, which further contributes to MZ B cell development in addition to enhancing MZ B cell metabolic fitness.

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