The role of Tfh-derived LIF in B cell responses

Germinal center (GC) B-cells are critical for long-lived antibody responses and their induction and maintenance depends on T follicular helper (Tfh) cells. Increasing BCR affinity through somatic hypermutation favours a shift from memory B cells to plasma cell output over time. The contribution of Tfh cells to this shift is unclear, with some evidence that their product IL-21 promotes plasma cell formation while limiting memory B cells. Here we show that human and mouse Tfh cells produce leukemia inhibitory factor (LIF) and expression increases and sustains through late GC stages, after IL-21 has peaked. LIF signals directly in B and T-cells to enhance BCL6 expression, promote GC B cell responses and limit GC B cell apoptosis. In the absence of LIF, GCs, plasma cells and antibody affinity were reduced, while memory B cells did not change. LIF appeared more effective at inducing BCL6 in human memory B-cells compared to naive and GC B-cells. Unlike IL-21 that is abundantly expressed by both human follicular regulatory (CD25+) and helper (CD25-) T cells, LIF was selectively produced by CD25- Tfh. IL-21 and LIF activated STAT3 but only LIF induced type-I interferon responses and NFAT5 phosphorylation in B-cells. LIF emerges as an important determinant of long-lived antibody responses, with non-redundant roles in GC homeostasis