Cell Type-Specific Expression and Functional Specialization of CXCL12 Isoforms

The chemokine CXCL12 plays central roles in hematopoiesis, immune cell trafficking and adaptive responses, yet how its multiple isoforms contribute to these processes remains poorly understood. Here we delineate distinct expression patterns and physiological functions of the CXCL12 α and γ isoforms within bone marrow niches and immune organs. By combining genetic deletion, expression studies and functional assays, we show that the strongly matrix-anchored CXCL12γ predominates in endothelial cells and controls both the size of the hematopoietic stem cell pool and mature lymphocyte entry into the bone marrow parenchyma. In contrast, we found that the more diffusible CXCL12α is the major isoform produced by non-endothelial stromal cells, and particularly by the CXCL12-expressing reticular cells of germinal centers where it is uniquely concentrated in the dark zone and supports antibody affinity maturation. These results uncover an isoform-specific division of labor in the CXCL12 system and point to cell type-specific differential splicing as an important determinant for the control of the diverse biological roles of CXCL12, highlighting the importance of ECM attachment as a regulator of chemokine function.