Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development.
Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor alpha (IL-7Ralpha) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7Ralpha, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7-independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l(-/-) mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in Flt3l(-/-)Il7r(-/-) mice. These findings implicate a permissive role of cytokine receptors of the hematopoietin and tyrosine kinase families in early T lymphopoiesis.
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
Christina T
CT
Jensen
Charlotta
C
Böiers
Shabnam
S
Kharazi
Anna
A
Lübking
Tobias
T
Rydén
Mikael
M
Sigvardsson
Ewa
E
Sitnicka
Sten Eirik W
SE
Jacobsen
D000818:Animals; D016207:Cytokines / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology*; D015851:Interleukin-7 / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D018121:Receptors, Cytokine / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D015851:Interleukin-7; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; C084881:flt3 ligand protein; C415350:interleukin-7 receptor, alpha chain; D020794:Receptor Protein-Tyrosine Kinases; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse