Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 31, Pages E2905-E2914Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1304859110
Keywords
CD4 T cells; CD8 T cells
Categories
Funding
- MRC (United Kingdom) [U117573801]
- National Institutes for Health [R01AI093870]
- Medical Research Council [MC_PC_13055, MC_U117573801] Funding Source: researchfish
- MRC [MC_PC_13055, MC_U117573801] Funding Source: UKRI
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It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable similar to 75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis.
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