The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells

Abstract

It is generally accepted that the avidity of TCR for self Ag/MHC determines the fate of immature thymocytes. However, the contribution of the quantity of TCR signal to T cell selection has not been well established, particularly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3ζ-deficient (DO-Tg/ζKO) mice in which T cells have a reduced TCR on the cell surface. In DO-Tg/ζKO mice, very few CD4 single positive (SP) thymocytes developed, indicating that the decrease in TCR signaling resulted in a failure of positive selection of DO-Tg thymocytes. Administration of the peptide Ag to DO-Tg/ζKO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO-Tg CD8 SP cells emerged at lower doses of Ag. TCR signal-dependent, sequential commitment from CD8+ SP to CD4+ SP was also shown in a class I-restricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and further suggest that weak signal directs positively selected T cells to CD8 lineage and stronger signal to CD4 lineage.

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

“…It has been shown that positive and negative selection of thymocytes are quantitatively regulated by TCR signals [11][12][13][14]. T cells ignore a very weak signal and cause default cell death.…”

“…Negative selection in TCR-Tg mice may be induced by very strong signals with high-affinity TCR, which cannot be rescued by CTLA-4 expression, whereas Mls-and anti-CD3 Abinduced DP cell depletion may represent rather weak negative selection, resulting in the rescue in FL-Tg mice. This hypothesis could be proven by analyzing a system in which TCR signals to induce thymic selection from positive to negative can be manipulated by changing the concentration of Ag in TCR-Tg mice [13].…”

“…The fate of thymocytes by these selections is determined by the strength and duration of TCR signals upon the recognition of self-peptides. As the TCR signal becomes stronger and longer, depending on the affinity of the TCR as well as the nature and concentration of the peptides, the consequence of selection is gradually shifted from default cell death as non-selection to positive selection of CD8 + cells, positive selection of CD4 + cells, and then negative selection as clonal deletion [11][12][13][14]. Therefore, when an activation signal through the TCR in a thymocyte is altered by other signals such as a costimulation signal, the selection and fate of cells with certain windows of affinity of TCRpeptide/MHC interaction will be altered.…”

Impaired Generation of CD8+ Thymocytes in Ets-1-Deficient Mice

“…Still, it is not clear whether the mechanisms governing lineage commitment and down-regulation of CD4 or CD8 are distinct from those governing the selection process. Although evidence for a stochastic model of lineage commitment has been provided (17)(18)(19)(20), it has become more generally accepted that lineage commitment is dictated by the quality of signal emanating from the TCR/coreceptor complex that is productively engaged (21)(22)(23)(24)(25)(26)(27). Most recently, a "kinetic signaling" model of lineage commitment has been put forth suggesting that the CD4 coreceptor does not transduce unique "instructional" signals per se, but that sustained signals from the TCR/ CD4 coreceptor complex appear required for commitment to the CD4 lineage (28).…”

Cathepsin-L Influences the Expression of Extracellular Matrix in Lymphoid Organs and Plays a Role in the Regulation of Thymic Output and of Peripheral T Cell Number

“…The intracellular signaling pathways stimulated by integrin-ligand binding are shared by a number of other surface receptors expressed on thymocytes, including growth factor receptors, the TCR-CD3 complex, CD4 and CD8 (54). It has been reported that the intensity of signals appears to be crucial for positive selection and CD4/CD8 lineage commitment (55)(56)(57)(58)(59). Stronger and/or longer TCR signals may be required for CD4 than for CD8 lineage commitment (56 -60).…”