Defects in Early Lymphopoiesis Contribute to Sepsis-Induced Thymic Atrophy

• Published in: Blood 2014-12, Vol.124 (21), p.4328-4328
• Main Authors: Kong, Yaxian, Zhang, Weimei, Li, Yajie, Zheng, Hong, Kosan, Christian, Zeng, Hui
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.4328.4328

Emergency hematopoiesis is important for the host to replenish the loss of immune cells and meet the enhanced demand for appropriate immune cells during acute infection. Previous studies have explored several intrathymic mechanisms that negatively affect thymopoiesis and subsequentlycontribute to sepsis-associated immunosuppression. However, the extrathymic mechanisms remain poorly understood. In line with previous studies, the mice subjected to cecal ligation and puncture developed severe T-cell lymphopenia. Moreover, lower numbers of T cell receptor circles excision circles (TRECs) were detected in septic mice when compared with control mice, which suggested a decrease in T-cell output from the thymus. Gross and histologic examinations and total thymus cellularity were in agreement with decreased thymic output. Next, we investigated whether sepsis affected intrathymic progenitors. There was a dramatic decline in the proportions as well as absolute numbers of early T-lineage progenitors (ETPs, Lin-CD117+CD44-CD25-CD127-) in the thymi of septic mice (Figure 1 A). Notably, the percentage of ETPs correlated positively with the number of thymocytes (r=0.6481, p=0.0005, Figure 1B). However, septic mice did not show a decrease in the number of bone marrow (BM) precursor cells. Instead, transwell migration assay exhibited that compared with cells from control mice, lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs) from septic mice exhibited significantly reduced chemotaxis towards chemokine gradients, including CCL19, CCL25, and P-selectin. In line with these results, real-time PCR revealed decreased mRNA levels of CCR7 (receptor of CCL19 and CCL21), CCR9 (receptor of CCL25), and P-selectin glycoprotein ligand (PSGL)1 in BM LMPPs and CLPs from septic mice when compared with control mice. In contrast, thymic tissues of septic mice expressed higher levels of mRNA for CCL19, CCL21 and CCL25. Thus, decreased expression of chemokine receptors might contribute to impaired chemotaxis of BM lymphoid progenitors in septic mice. To investigate whether sepsis affected the differentiation program of hematopoietic stem and progenitor cells (HSPCs), we compared the mRNA expression profiles of key regulators of lymphoid differentiation in HSPCs from control and septic mice. hematopoietic stem cells (HSCs), multipotent progenitors (MPPs), LMPPs and CLPs from mice challenged with cecal ligation and puncture exhibited downregulated expression