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Apoptotic Diminution of Immature Single and Double Positive Thymocyte Subpopulations Contributes to Thymus Involution
Christoph Netzer1, Tilo Knape, Laura Kuchler
1*Institute of Biochemistry I-Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany †Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Frankfurt, Germany ‡Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany §Department of Neurology, University Hospital Frankfurt, Frankfurt, Germany ||Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina.
To generate and maintain functional T-cell receptor diversity, thymocyte development is tightly organized. Errors in this process may have dramatic consequences, provoking, for example, autoimmune diseases. Probably for this reason, the thymus reacts to septic stress with involution, decreasing the numbers of thymocytes. Because it is still unclear which thymocyte subpopulation contributes to thymus involution and whether thymocyte emigration is altered, we were interested to clarify this question in detail. Here, we show, using the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis, that predominantly immature thymocytes are reduced. The number of immature single positive thymocytes was most marked diminished (CLP: 6.54 × 10 ± 3.79 × 10 vs. sham: 4.54 × 10 ± 7.66 × 10 cells/thymus [24 h], CLP: 2.60 × 10 ± 2.14 × 10 vs. sham: 2.17 × 10 ± 1.90 × 10 cells/thymus [48 h]), and was consequently associated with the highest rate of apoptosis (8.4 [CLP] vs. 2.2% [sham]), the reduction in double positive thymocytes being associated with a smaller apoptotic response (number, CLP: 2.33 × 10 ± 1.38 × 10 vs. sham: 1.07 × 10 ± 2.72 × 10 cells/thymus [24 h], CLP: 2.34 × 10 ± 9.08 × 10 vs. sham: 3.5 × 10 ± 9.62 × 10 cells/thymus [48 h]; apoptosis: 2.5% [CLP] vs. 0.7% [sham]). Analysis of T-cell receptor excision circles revealed that the emigration of mature thymocytes was not inhibited. Real-time qPCR analysis revealed upregulation of pro-apoptotic Bim expression and suggested interference between Notch receptor expression on thymocytes and the respective ligands on thymic stromal cells during CLP-dependent sepsis, which might be responsible for the altered thymocyte viability in CLP-dependent sepsis.
To generate and maintain functional T-cell receptor diversity, thymocyte development is tightly organized. Errors in this process may have dramatic consequences, provoking, for example, autoimmune diseases. Probably for this reason, the thymus reacts to septic stress with involution, decreasing the numbers of thymocytes. Because it is still unclear which thymocyte subpopulation contributes to thymus involution and whether thymocyte emigration is altered, we were interested to clarify this question in detail. Here, we show, using the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis, that predominantly immature thymocytes are reduced. The number of immature single positive thymocytes was most marked diminished (CLP: 6.54 × 10 ± 3.79 × 10 vs. sham: 4.54 × 10 ± 7.66 × 10 cells/thymus [24 h], CLP: 2.60 × 10 ± 2.14 × 10 vs. sham: 2.17 × 10 ± 1.90 × 10 cells/thymus [48 h]), and was consequently associated with the highest rate of apoptosis (8.4 [CLP] vs. 2.2% [sham]), the reduction in double positive thymocytes being associated with a smaller apoptotic response (number, CLP: 2.33 × 10 ± 1.38 × 10 vs. sham: 1.07 × 10 ± 2.72 × 10 cells/thymus [24 h], CLP: 2.34 × 10 ± 9.08 × 10 vs. sham: 3.5 × 10 ± 9.62 × 10 cells/thymus [48 h]; apoptosis: 2.5% [CLP] vs. 0.7% [sham]). Analysis of T-cell receptor excision circles revealed that the emigration of mature thymocytes was not inhibited. Real-time qPCR analysis revealed upregulation of pro-apoptotic Bim expression and suggested interference between Notch receptor expression on thymocytes and the respective ligands on thymic stromal cells during CLP-dependent sepsis, which might be responsible for the altered thymocyte viability in CLP-dependent sepsis.
