The timing of TCRα expression critically influences T cell development and selection

Troy A Baldwin,Kristin A Hogquist,Michelle M Sandau,Stephen C Jameson

doi:10.1084/jem.20050359

Troy A Baldwin, Kristin A Hogquist + Show 2 more

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https://doi.org/10.1084/jem.20050359

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Abstract

Sequential rearrangement of the T cell receptor for antigen (TCR) β and α chains is a hallmark of thymocyte development. This temporal control is lost in TCR transgenics because the α chain is expressed prematurely at the CD4−CD8− double negative (DN) stage. To test the importance of this, we expressed the HYα chain at the physiological CD4+CD8+ double positive (DP) stage. The reduced DP and increased DN cellularity typically seen in TCR transgenics was not observed when the α chain was expressed at the appropriate stage. Surprisingly, antigen-driven selection events were also altered. In male mice, thymocyte deletion now occurred at the single positive or medullary stage. In addition, no expansion of CD8αα intestinal intraepithelial lymphocytes (IELs) was observed, despite the fact that HY transgenics have been used to model IEL development. Collectively, these data establish the importance of proper timing of TCR expression in thymic development and selection and emphasize the need to use models that most accurately reflect the physiologic process.

Highlights

The CD44/CD25 profile of double negative (DN) thymocytes from HYcd4 mice was similar to HY␤-only mice, which display a slight acceleration through the DN subsets (Fig. 1 B, bottom)
By expressing HY T cell receptor for antigen (TCR)␣ at the double positive (DP) stage, we found a similar percentage of annexin Vϩ DN4 cells as in wild-type mice, whereas the early TCR␣ expression observed in conventional HY mice resulted in a 5–10-fold increase in annexin Vϩ DN4 cells (Fig. 2 A, right)
Our data indicate that early expression of the TCR affects several properties in TCR transgenic mice

Summary

Introduction

A key feature of these selective events and a hallmark of T cell development is the ordered and sequential rearrangement and expression of the TCR␤ and TCR␣ chains, respectively This highly regulated process ensures the production of a clonally expressed repertoire with a minimum of energy expenditure. Using a Cre/loxbased conditional strategy, we expressed the HY TCR␣ at the DP stage of development (HYcd mice) In this model, the defects in ␤-selection and lineage commitment observed in conventional HY transgenics were corrected. The prominent expansion of CD8␣␣ϩ intraepithelial lymphocytes (IELs) observed in conventional HY male mice was not apparent in HYcd mice These observations suggest that certain properties of conventional TCR transgenics are nonphysiologic and demonstrate that T cell selection is critically influenced by the appropriate timing of TCR␣ expression

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Conclusion