A Molecular Map of T Cell Development

Self Cite

How TCR and non-TCR signals are integrated by thymocytes to generate a decision to undergo either positive or negative selection remains incompletely understood. Recent evidence suggests that TCR signal transduction changes its quality during thymocyte maturation, but whether the contributions of various cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the possible selective roles of specific costimulatory pathways in induction of differentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD4+CD8+ thymocyte differentiation as measured by CD69 up-regulation/coreceptor down-modulation was conducted in parallel with an analysis of induction of death. Using transfected cells varying in their surface display of ICAM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation without substantially affecting induction of death among CD4+CD8+ cells, a property that is lost as thymocytes mature further. In contrast, B7 engagement enhances both cell activation and death in parallel. Based on these data, we propose that the high level of ICAM-1 on cortical epithelial cells plays a special role in opening a window between TCR signaling for differentiation vs death, permitting efficient initiation of positive selection on epithelial ligands. In contrast, late CD28-dependent cosignaling on hemopoietic cells in the medulla would help enforce negative selection by augmenting the effects of TCR engagement by low levels of high affinity ligands.

Section: Differing Roles Of Icam-1 and B71 Costimulation In Dp Vs Masupporting

confidence: 91%

Opening a Window on Thymic Positive Selection: Developmental Changes in the Influence of Cosignaling by Integrins and CD28 on Selection Events Induced by TCR Engagement

Lucas

Germain

2000

Self Cite

“…The short length of peripheral TCR BV CDR3 had been noted previously (32), but it was not clear whether this was a function of the rearrangement mechanism itself or of a shortening postrearrangement. The selection for thymocytes with shorter CDR3 can be observed at the CD3 high DP stage, strongly supporting the precursor relationship between CD3 low and CD3 high DP cells (10,15,28,29).…”

Section: Discussionsupporting

confidence: 57%

“…These took advantage of a propensity of the ␤-chain to pair with ␣-chains similar to that with which it was paired in the hybridoma of origin (15,23). This identifies a stage that can be referred to as ␣ selection.…”

Section: Analysis Of Tcr V ␣-Chain Genes During Thymocyte Maturationmentioning

confidence: 99%

See 1 more Smart Citation

Thymocyte Maturation: Selection for In-Frame TCR α-Chain Rearrangement Is Followed by Selection for Shorter TCR β-Chain Complementarity-Determining Region 3

Yassai

Gorski

2000

Thymocyte maturation consists of a number of stages, the goal of which is the production of functioning T cells that respond to foreign antigenic peptides using their clonotypic receptors. Selection of a productively rearranged TCR β-chain is the first stage in the process and occurs at the double-negative to double-positive (DP) transition. Later maturation stages are based on changes in markers such as CD5, CD69, or IL-7R. A stage in which α-chains are selected has also been identified using β-chain transgenic mice. Here we identify two additional selection stages in human thymocytes based on characteristics of the TCR. α selection is measured directly by identification of in-frame rearrangements and is associated with the appearance of CD3 on the DP thymocyte surface. The next stage has not yet been described and involves selection of thymocytes that express shorter TCR β-chain complementarity-determining region 3 (CDR3). This stage is associated with the acquisition of high levels of CDR3 by DP cells and the transition to SP thymocytes. The extent of CDR3 length selection observed is a function of the TCR V and J genes. We propose that CDR3 length selection is based on recognition of the MHC. Thus, there exist limitations on the allowable length of that portion of the TCR most intimately in contact with MHC and peptide. This may be a physical representation of positive selection.

“…By contrast, negative and positive selection do not appear to be strictly restricted to the cortex or medulla (24,33), even if negative selection-related apoptotic cells have been exclusively observed in the medulla (34). Furthermore, TCR repertoire shaping by positive selection, while mainly detected in the cortex (35), seems to continue in the medulla (36).…”

Section: Discussionmentioning

confidence: 99%

Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes

Campion

Lucas

Dautigny

et al. 2002

Self Cite

In normal mice, single-positive thymocytes proliferate before being exported into the peripheral T cell pool. We measured the in vivo proliferation rates of mature thymocytes in several TCR transgenic mice. Different monoclonal TCR transgenic single-positive thymocytes proliferated at different rates in a given MHC context. Conversely, mature thymocytes expressing a given TCR, generated in mice of different MHC haplotypes, also showed different rates of proliferation. In p59fyn-deficient mice, the proliferation rate of mature thymocytes was diminished. Thus, premigrant thymocyte expansion is TCR mediated and depends on TCR affinity for self peptide/MHC ligands. In addition, we show that mature thymocyte expansion is clonotypic, increases the daily thymic T cell output, and modifies the TCR repertoire of newly produced T cells.