Deregulated TCR alpha beta T cell population provokes extramedullary hematopoiesis in mice deficient in the common gamma chain.
Deficiency of the cytokine receptor common gamma chain (gamma c) 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 gamma c. These extramedullary changes were not secondary to bone marrow failure or to an inability to maintain circulating blood counts. These results suggested that gamma c-dependent cytokine signaling pathways modulate hematopoietic development. An intrinsic defect in gamma c- hematopoietic stem cell commitment appeared unlikely, as fetal liver hematopoiesis was unaltered in gamma c- embryos. Furthermore, the absence of natural killer cells in gamma c- mice was not responsible for the observed hematopoietic changes. Peripheral TCR alpha beta T cells from gamma c- 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 gamma c- mice reduced splenic and circulating hematopoietic precursor frequencies to normal levels. These results clearly implicate a deregulated TCR alpha beta T cell population in the observed hematopoietic changes in gamma c- mice, and emphasize the importance of gamma c-dependent cytokine interactions in modulating mature T cell responses.
Sharara
L I
LI
INSERM U429, Hôpital Necker, Paris, France.
Andersson
A
A
Guy-Grand
D
D
Fischer
A
A
DiSanto
J P
JP
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000502:physiology; D005333:Fetus; D006411:Hematopoiesis, Extramedullary / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D016693:Receptors, Antigen, T-Cell, alpha-beta; D018121:Receptors, Cytokine