RESUMEN
The leukocyte-specific tyrosine phosphatase, CD45, severely impacts T cell development and activation by modulating TCR signaling. CD45-deficient (CD45KO) mice have reduced peripheral T cell numbers where CD8 T cells are underrepresented. In this article, we show that CD45KO mice are unable to support efficient homeostatic proliferation, affecting CD8 T cells more than CD4 T cells. Using CD45-RAG1 double-deficient (45RAGKO) mice, we show that lymphopenia-induced proliferation (LIP) of CD45-sufficient T cells is defective in a host environment lacking CD45 on innate immune cells. We identify two deficiencies in the 45RAGKO mice that affect LIP. One involves CD11c(+) cells and the second the production of IL-7 by lymphoid stromal cells. CD45KO dendritic cells were not defective in foreign Ag-induced T cell proliferation, yet CD45KO CD11c(+) cells were unable to rescue the spontaneous LIP in the 45RAGKO mice. This was in contrast with the CD45-sufficient CD11c(+) cells that partially rescued this spontaneous proliferation and did so without affecting IL-7 levels. The absence of CD45 also led to reduced IL-7 production by lymphoid stromal cells, suggesting an indirect effect of CD45 on innate immune cells in influencing IL-7 production by lymphoid stromal cells. These findings demonstrate a novel role for CD45 on innate immune cells in promoting lymphopenia-induced T cell proliferation and suggest that innate immune cells may communicate with stromal cells to regulate IL-7 production.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos Comunes de Leucocito/inmunología , Activación de Linfocitos/inmunología , Linfopenia/inmunología , Animales , Antígeno CD11c/biosíntesis , Relación CD4-CD8 , Diferenciación Celular/inmunología , Proliferación Celular , Células Dendríticas/inmunología , Inmunidad Innata , Interleucina-7/biosíntesis , Antígenos Comunes de Leucocito/biosíntesis , Antígenos Comunes de Leucocito/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Células del Estroma/inmunologíaRESUMEN
Red blood cells are generated daily to replenish dying cells and maintain erythrocyte homeostasis. Erythropoiesis is driven by erythropoietin and supported by specialized red pulp macrophages that facilitate enucleation. Here we show that the leukocyte-specific tyrosine phosphatase CD45 is downregulated in late erythroid development, yet it regulates the CD71+TER119+ progenitor pool, which includes the Pro E, Ery A, and Ery B populations. The CD71+TER119+ progenitors are a major splenic population in neonates required for extramedullary erythropoiesis, to meet the high demand for red blood cells during growth. This population decreases as the mice mature, but this was not the case in CD45-deficient mice, which maintained a high level of these progenitors in the spleen into adulthood. Despite these increased erythroid progenitors, CD45-deficient mice had normal numbers of mature red blood cells. This was attributed to the increased proliferation of the Pro E and Ery A populations and the increased apoptosis of the CD71+TER119+ population, as well as an increased turnover of circulating red blood cells. The expansion of the CD71+TER119+ population in the absence of CD45 was attributed to increased numbers of red pulp macrophages producing erythropoietin in the spleen. Thus, CD45 regulates extramedullary erythropoiesis in the spleen.