CD137 ligand reverse signaling skews hematopoiesis towards myelopoiesis during aging

CD137 is a costimulatory molecule expressed on activated T cells. Its ligand, CD137L, is expressed on the surface of hematopoietic progenitor cells, and upon binding to CD137 induces reverse signaling into hematopoietic progenitor cells promoting their activation, proliferation and myeloid differentiation. Since aging is associated with an increasing number of myeloid cells we investigated the role of CD137 and CD137L on myelopoiesis during aging. Comparing 3 and 12 months old WT, CD137^−/− and CD137L^−/− mice we found significantly more granulocytes and monocytes in the bone marrow of older WT mice, while this age-dependent increase was absent in CD137^−/− and CD137L^−/− mice. Instead, the bone marrow of 12 months old CD137^−/− and CD137L^−/− mice was characterized by an accumulation of hematopoietic progenitor cells, suggesting that the differentiation of hematopoietic progenitor cells became arrested in the absence of CD137L signaling. CD137L signaling is initiated by activated CD137-expressing, CD4⁺ T cells. These data identify a novel molecular mechanisms underlying immune aging by demonstrating that CD137-expressing CD4⁺ T cells in the bone marrow engage CD137L on hematopoietic progenitor cells, and that this CD137L signaling biases hematopoiesis towards myelopoiesis during aging.