Thymocyte development in major histocompatibility complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages.

Abstract

The mechanism resulting in commitment of precursor cells in the thymus to either the CD4 or CD8 lineage remains poorly understood. In principle, this may reflect a stochastic process or may reflect instructional signals from host major histocompatiblity complex (MHC) molecules. We have examined the role of MHC products in subset commitment by using mice deficient in class I or class II MHC products. Normal numbers of committed CD4 intermediates (CD4+ CD8I0) develop in the thymus in the absence of class II molecules. Similarly, CD8 transitional cells (CD4IOCD8+) are present in the thymus of mice lacking class I products. These findings suggest that commitment of CD4+8+ precursor cells to either lineage is a stochastic process that does not depend on instructive signals from MHC molecules (i.e., expression of alternative differentiative options by uncommitted precursor cells is independent of this environmental signal). These studies also suggest that an interaction between the T-cell antigen receptor (TCR) and MHC molecules that is independent of CD4/CD8 coreceptor engagement enhances stochastic coreceptor downregulation substantially and leads to upregulation of TCR expression as a prelude to selective events that require joint coreceptor/TCR engagement. We suggest that this initial interaction molds the TCR repertoire of stochastically generated T-cell subsets toward recognition of self-MHC products.The thymus gives rise to two lineages of T lymphocytes that regulate immune responses. T cells that express the CD4+8-surface phenotype (CD4 cells) recognize antigen associated with class II major histocompatibility complex (MHC) products and mediate helper activity. T cells that express the CD4-8+ phenotype (CD8 cells) recognize antigen associated with class I MHC products and mediate killer activity (reviewed in ref. 1).The developmental steps resulting in the formation of these independent T-cell lineages remain poorly understood. Precursor cells in the thymus that expresses the CD4+8+ surface phenotype [termed double-positive (DP) thymocytes (2, 3)] downregulate either CD4 or CD8 to generate lineagecommitted intermediaries expressing the CD4+CD8l0 or CD41OCD8+ phenotype (4, 5). Development of mature singlepositive (SP) CD4 or CD8 progeny depends upon positive selection by intrathymic MHC molecules (6-9). The timing and regulation of this process have been studied primarily by using mice that express transgenic T-cell antigen receptors (TCRs) and/or coreceptors (CD4 and CD8) (10-13). Although this experimental model has contributed substantially to our understanding of thymocyte development, interpretation of these studies may be complicated by abnormally highThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.or premature expression of these transgenic products on thymocytes.Two general models have been proposed to explain the mechanism by which a si...

Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands

“…In line with this, pre-TCR ligand independence previously ascribed to pT␣ charge-based receptor oligomerization has been impugned (13). The liganddependent pre-TCR pathway operates in parallel with mechanisms that foster "tonic" developmental progression (12), explaining why pre-TCR ectodomain deletions (14) or MHC loss (15) does not abrogate thymocyte progression.…”

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

“…Models of thymocyte development based on the role of TCRdependent selection signals include stochastic (48)(49)(50)(51) and instructional (52) mechanisms. More recent modeling emphasizes the strength and͞or duration of TCR-based signals (13,53).…”

Interaction of 2C T Cells with a Hybrid Ld Molecule Bearing an α3 Domain Derived from the Class Ib Molecule, Qa‐2

“…An analogous experiment performed in MHC-deficient mice recapitulates these findings. Thus, the number of CD4 þ and CD8 þ T cells is dramatically reduced in Cl II-and Cl I-deficient mice, respectively [16][17][18][19].…”