Development of the CD4 and CD8 lineage of T cells: instruction versus selection.

Abstract

T cells bearing the alpha beta T cell receptor (TCR) can be divided into CD4+8‐ and CD4–8+ subsets which develop in the thymus from CD4+8+ precursors. The commitment to the CD4 and CD8 lineage depends on the binding of the alpha beta TCR to thymic major histocompatibility complex (MHC) coded class II and class I molecules, respectively. In an instructive model of lineage commitment, the binding of the alpha beta TCR, for instance to class I MHC molecules, would generate a specific signal instructing the CD4+8+ precursors to switch off the expression of the CD4 gene. In a selective model, the initial commitment, i.e. switching off the expression of either the CD4 or the CD8 gene would be a stochastic event which is then followed by a selective step rescuing only CD4+ class II and CD8+ class I specific T cells while CD4+ class I and CD8+ class II specific cells would have a very short lifespan. The selective model predicts that a CD8 transgene which is expressed in all immature and mature T cells should rescue CD4+ class I MHC specific T cells from cell death. We have performed experiments in CD8 transgenic mice which fail to support a selective model and we present data which show that the binding of the alpha beta TCR to thymic class I MHC molecules results in up‐regulation of the TCR in the CD4+8+ population. Therefore, these experiments are consistent with an instructive model of lineage commitment.

Detailed analysis of gene expression during development of T cell lineages in the thymus

“…More recent modeling emphasizes the strength and͞or duration of TCR-based signals (13,53). According to the strength of signal model, increased signaling through CD4-class II interactions promotes CD4 lineage commitment, whereas weaker signals underlie a CD8 default pathway (52,54,55). Our experiments do not distinguish between the impact of MHC class II-and class I-dependent signaling in early lineage commitment.…”

Overexpression of AML1 Transcription Factor Drives Thymocytes into the CD8 Single-Positive Lineage

“…One model is that overexpression of AML1 might have redirected the fate of otherwise CD4 SP-oriented DP thymocytes into the CD8 SP lineage. According to the instruction model, the affinities of the TCR for class II and class I molecules guide the differentiation of DP cells into the CD4 SP and CD8 SP lineages, respectively (31,32). It is hypothesized that DP cells receive signals from their CD4/TCR or CD8/TCR molecules and distinguish each signal based on its strength and duration (33)(34)(35).…”

Regulation of AP-1 and NFAT Transcription Factors during Thymic Selection of T Cells

“…This could be a mechanism to prevent the activation of DP thymocytes before selection has taken place. (3,32,33,45,55,57,62) as well as MHC class II-and class I-deficient mice (10, 16) has shown that this decision is mediated by positive selection that is dictated by the interaction of a specific TcR, associated with a CD4 or CD8 coreceptor, with the appropriate positive-selecting MHC class II or class I, respectively, on epithelial cells of the thymus.Two models of thymocyte selection have been proposed to explain the decision of a DP cell to commit to the CD4 or CD8 lineage (6,50,66), although this question is still open. The instructive model proposes that positive selection occurs at the DP stage of maturation.…”

“…Two models of thymocyte selection have been proposed to explain the decision of a DP cell to commit to the CD4 or CD8 lineage (6,50,66), although this question is still open. The instructive model proposes that positive selection occurs at the DP stage of maturation.…”