Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity

Abstract

The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1-deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naïve T cells but, paradoxically, mildly elevated serum antibody titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. Here we found that early T-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established antigen-specific IgG1 titers in Mst1-deficient mice decayed more readily due to a loss of antigen-specific, but not the overall, bone marrow plasma cells. Despite the impaired affinity and longevity of antigen-specific antibodies, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138+Blimp1+ splenic plasma cell populations yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high affinity humoral immunity and that prophylactic antibody replacement therapy can be beneficial to the patients.

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

“…A potential therapeutic strategy to circumvent this problem is to combine immune checkpoint and methylase inhibitors ( 30 ). PD-1 and CTLA4 have been implicated in various pathways related to immune function ( 52 , 53 ). We carried out GSEA to identify clinically relevant pathways that may provide clues for future research.…”

Hippo Signal Transduction Mechanisms in T Cell Immunity

“…If this is true, mice harboring Mst-deficient T cells would have increased β-catenin when activated by TCR or Wnt and display opposite phenotypes that are seen in mice lacking TCF1 or β-catenin in T cells. In support of this notion, Th2 and Tfh responses were elevated in Mst1 knockout mice (19,65). On the other hand, there was no gross defect in T cell development in mice lacking Mst1 and Mst2 in the T cell compartment-it was rather a migration defect after maturation.…”

“…Despite lymphopenia, Mst1-deficient mice and humans have normal or elevated levels of serum immunoglobulins (9,10,19). At least part of this can be attributed to enhanced T follicular helper cell activities including IL-4, IL-21, and CD40L (19). How Mst1-deficiency augments Tfh function is not clear.…”

“…However, the fact that patients who received prophylactic Ab replacement therapy were protected from infections (10-12) suggests that the apparently normal levels of class-switched Abs may not provide protection against infections. In support of this, mice lacking Mst1 cannot produce long-lived high-affinity Abs even when they had enough numbers of T cells and B cells to support initial Ab production (19). This appears to be due to hyperactive T follicular helper cells supporting premature transition of germinal center B cells into plasma cells, which fail to sustain themselves in the bone marrow (19).…”

“…In support of this, mice lacking Mst1 cannot produce long-lived high-affinity Abs even when they had enough numbers of T cells and B cells to support initial Ab production (19). This appears to be due to hyperactive T follicular helper cells supporting premature transition of germinal center B cells into plasma cells, which fail to sustain themselves in the bone marrow (19).…”