The Zinc-Sensing Receptor GPR39 Is a Master Regulator of Immune Reconstitution after Bone Marrow Transplant in the Thymus and in the Bone Marrow

Reconstitution of the adaptive immune system after lymphodepleting therapies, such as chemotherapy and radiotherapy, is a complex phenomenon involving the regeneration of bone marrow (BM)-derived progenitors and their maturation into mature B and T lymphocytes in the BM and thymus, respectively. Although the thymus has tremendous capacity to regenerate itself after acute damage, this capacity declines over lifespan leading T cell reconstitution after hematopoietic stem cell transplant (HSCT) usually take months to years. Prolonged T cell lymphopenia is thus an important contributor to transplant-related morbidity and mortality. Furthermore, any defect in T cells is associated with poor activation of B cells and low levels of immunoglobulin. Unlike other hematopoietic cell deficiencies, there are currently no approved therapies to treat lymphopenia.

The availability of Zinc (Zn), the second most abundant trace element in our body, is crucially linked to the everyday production of T cells and to the capacity of the thymus to regenerate. In a recent study, our group demonstrated that the zinc-sensing G-protein coupled receptor GPR39 is involved in thymic regeneration (Iovino et al. Blood, 2022) by stimulating endogenous regeneration mechanisms. Within the thymus, GPR39 is expressed mostly by stromal cells, with stimulation promoting production of the pro-regenerative factor bone morphogenetic protein 4 (BMP4) from thymic endothelial cells (ECs). Importantly, directly targeting GPR39 with a small agonist molecule called TC-G1008 could be used in vivo to promote thymic reconstitution after HSCT.

Here, we show that in addition to its effects in the thymus, modulation of zinc signaling could also profoundly impact on pre-thymic hematopoiesis in the BM. In mice receiving a specialized zinc-deficient diet we observed that Zn deficiency caused a profound defect in the production of B cells into the BM. Moreover, in vivo administration of TC-G 1008 helped recovery of both B and T cells in old mice (16-18 mo), including their export into the periphery (Figure 1). Interestingly, we observed no differences in the myeloid granulocyte or monocyte populations, suggesting this is not a broad hematopoiesis phenotype but more restricted to lymphopoiesis. To confirm that faster B and T cells reconstitution arose from precursors and not from the expansion of already mature lymphocytes, 16-month-old C57BL/6 mice were transplanted from donors that expressed green fluorescent protein (GFP) under the control of RAG2 (RAG2-GFP): mice that received TC-G1008 after HSCT showed higher levels of GFP+ B and T cells into the periphery. We found that hematopoietic precursors including long term hematopoietic stem cells (LT-HSC), myeloid precursors (MP), and lymphoid progenitors all expressed GPR39; although more committed myeloid progenitors lost their expression of GPR39 as did B cells as they transitioned from the pro-B to the immature B cell stages. However, GPR39 expression was highest on many of the BM stromal cells, including ECs and mesenchymal stromal cells (MSC), but not osteoblasts. While preliminary, these studies suggest that GPR39 is a master regulator of immune regeneration, acting not only into the thymus but also in the BM. More data are needed to clarify whether the observed increased B cell regeneration is due to a direct effect of GPR39 on hematopoietic precursors or to an effect on the BM stromal cells. Our future studies will lay the groundwork for proposing GPR39 agonism as a promising strategy for immune regeneration.

These pre-clinical studies focusing on zinc biology not only help to identify the mechanisms that allow immune regeneration after acute injury such as that caused by the conditioning required for successful HSCT, but also offer a novel clinical approach to ameliorate lymphopenia due to aging, infectious disease, chemotherapy or radiation injury.

No relevant conflicts of interest to declare.