Deregulated TCRαβ T cell population provokes extramedullary hematopoiesis in mice deficient in the common γ chain

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Abstract
Deficiency of the cytokine receptor common γ chain (γc) results in abnormal lymphoid development and a severe immunodeficiency disease due to the combined loss of the receptors for interleukins (IL)-2, -4, -7, -9, and -15. We have observed the development of secondary hematopoiesis with circulating hematopoietic progenitor cells in adult mice harboring a null mutation in γc. These extramedullary changes were not secondary to bone marrow failure or to an inability to maintain circulating blood counts. These results suggested that γc-dependent cytokine signaling pathways modulate hematopoietic development. An intrinsic defect in γc− hematopoietic stem cell committment appeared unlikely, as fetal liver hematopoiesis was unaltered in γc− embryos. Furthermore, the absence of natural killer cells in γc− mice was not responsible for the observed hematopoietic changes. Peripheral TCRαβ T cells from γc− mice were characterized by an activated phenotype (CD62Llo, CD44hi, CD69hi) and showed increased levels of transcripts for hematopoietic stimulating cytokines, including IL-3 and granulocyte/macrophage-colony-stimulating factor. A predominance of these cells was detected in the bone marrow, suggesting a role for residual T cells in the enhanced hematopoiesis. Strikingly, the elimination of residual T cells from γc− mice reduced splenic and circulating hematopoietic precursor frequencies to normal levels. These results clearly implicate a deregulated TCRαβ T cell population in the observed hematopoietic changes in γc− mice, and emphasize the importance of γc-dependent cytokine interactions in modulating mature T cell responses.