Positive Selection of Thymocytes

Abstract

The requirement for immature thymocytes to demonstrate that their surface αβ T cell receptors (TCRs) have some reactivity to self-MHC class I or class I1 molecules is the barrier enforced by positive selection. Positively selected thymocytes are not driven to proliferate, and their receptors do not mutate away from self-recognition. Instead, cells are rescued from programmed cell death on the basis of self-recognition and go on to serve in the periphery as self-tolerant T cells. This different response in immature versus mature T cells to recognition of antigen through an unmutated TCR may be controlled by poorly understood changes in the trigger ability of the cells. Most αβ TCR thymocytes simply do not pass this test. Cells that initially fail positive selection may briefly continue to rearrange TCR a chain genes and finally succeed in expressing a selectable TCR. However, most DP thymocytes undergo a programmed cell death, ensuring that the selected repertoire is reactive with foreign peptides presented by self- MHC molecules. The nature of the signal triggered by the TCR-self-MHC interaction that rescues thymocytes from death remains an enigma. The interaction between the TCR and its MHC ligands that stimulates positive selection in fetal thymus organ culture (FTOC) is so weak that it does not stimulate any measurable signaling in mature T cells. For this reason, mature T cells cannot serve as model systems for the signal transduction pathway operating in thymocytes selection as obtained from the ever-expanding use of genetically manipulated animal model systems to elucidate the role of various gene products in thymocytes selection. The second source is the use of in vitro reaggregate culture systems that allow the study of positive selection from separated stromal and stem-cell components, in which it may soon be possible to introduce probes directly into the DP stem cells for positive selection.