Final Report Summary - IMMEMO (Protective and pathogenic immunological memory and its organisation by stroma cells)
Immunological memory is a hallmark of adaptive immunity. Plasma cells provide protective immunity, through the continued secretion of pathogen-specific antibodies, while memory B and T lymphocytes, the reactive memory, provide effective secondary immune responses to recurrent pathogens. The dark side of immunological memory is its ability to drive chronic inflammatory diseases and allergies. Despite its relevance, little is known about how immunological memory is generated and maintained. We had originally described longlived memory plasma cells, residing and resting in the bone marrow in direct contact with mesenchymal stroma cells expressing CXCL12. These stroma cells organize survival niches for the memory plasma cell by attracting accessory cells, such as eosinophils, which provide plasma cell survival factors. This led to the entirely novel concept of maintenance of immunological memory by persistence of memory cells in dedicated stromal niches, resting in terms of activation, proliferation and mobility, and surviving as long as they receive survival signals from their environment. In the ERC-Immemo project, we extended this concept to memory T helper lymphocytes, cytotoxic memory lymphocytes and memory B lymphocytes. In mice and humans, we identified prominent populations of bone marrow resident memory lymphocytes, resting in survival niches organized by dedicated stromal cells. We could show that the data demonstrating homeostatic proliferation of memory lymphocytes are in all likelihood a BrdU-artifact. We obtained evidence that bone marrow resident memory lymphocytes efficiently and lifelong maintain memory to systemic antigens, like measles and mumps, in contrast to memory cells circulating in the blood, and memory cells residing in epithelial tissues. We identified signals involved in homing of memory cell precursors to the bone marrow, their differentiation into memory cells and their survival as resting cells, such as CXCL12/CXCR4, CD69, CD49d. In summary, results of Immemo have fundamentally challenged the previous dogma that immunological memory is maintained by homeostatic proliferation of circulating memory lymphocytes and by memory lymphocytes residing in the epithelial tissues. Immemo has shown that lifelong immunological memory, in particular to systemic antigens, is maintained in the bone marrow, by memory cells residing in dedicated survival niches organized by mesenchymal stromal cells, and resting in terms of activation, proliferation and mobility. This fundamental insight has considerable fundamental and practical implications. In Immemo, we have explored the implications for an understanding of how immunological memory drives chronic inflammatory diseases. Above all, we have identified autoreactive memory plasma cells as the driving force and unmet therapeutic challenge of refractory inflammatory autoimmune and allergic diseases. We have developed and translated into the clinics novel concepts for the selective depletion of plasma cells in antibody-mediated immune-diseases. Second, we have identified molecular adaptations of memory-effector CD4+ T helper cells to chronic antigen-exposure and inflammation, like the transcription factor Twist1 and the adaptorprotein Hopx, expression of which is selectively upregulated by Stat4 and T-bet, respectively, in repeatedly restimulated proinflammatory Th1 cells. Twist1 induces expression of the microRNA miR-148a, which inhibits expression of Bim, a pro-apoptotic protein. Twist1 thus promotes persistence of proinflammatory memory-effector cells and chronicity of inflammation. Hopx interacts with a number of enzymes required by proinflammatory Th cells to adapt their metabolism to an inflammatory environment. These molecular adaptations qualify as original and novel targets for the selective therapeutic ablation of proinflammatory effector-memory T cells.