Human Granulocyte-Macrophage Colony-Stimulating Factor (hGM-CSF) Induces Inhibition of Intrathymic T-Cell Development in hGM-CSF Receptor Transgenic Mice

Thymocytes show differential cytokine responses, depending on the stage of differentiation. Whether these responses are due to preferential cytokine receptor expression or due to downstream signaling mechanisms is unknown. In this study, we examined the relationship between receptor expression and T-cell proliferation or differentiation using thymocytes from transgenic mice constitutively expressing the human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor. Transgenic CD4- CD8-, CD4+ CD8-, and CD4- CD8+ cells proliferated when cultured with hGM-CSF in vitro, whereas CD4+ CD8+ cells failed to proliferate. To examine the effect of hGM-CSF receptor signaling on T-cell development, we used fetal thymic organ cultures. The addition of exogenous hGM-CSF resulted in the failure of CD4- CD8- cells to differentiate into CD4+ CD8+ cells. To more closely identify this maturational inhibition, we reconstituted normal fetal lobes with sorted pro-T-, pre-T-, or post-pre-T-precursor cells from transgenic mice. The addition of hGM-CSF to these cultures led to a block in both pro-T- and pre-T-cell differentiation, whereas the more mature post-pre-T cells differentiated normally. We propose that hGM-CSF receptor signaling during T-cell development results in a stage-specific inhibition of thymic precursor maturation.