Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor.

Abstract

SummaryPositive selection of T cells is a complex developmental process generating long-lived, functionally mature CD4+CD8 -and CD4-CD8 + cells from short-lived, immature CD4+CD8 + precursors. The process is initiated in the thymus by interaction of the o~ TCR with molecules encoded by the MHC, occurs without cell division, and involves rescue from programmed cell death (PCD), as well as induction of differentiation and maturation of selected presursors. It is unclear whether development of small, positively selected CD4 + CD8 § thymocytes (characterized by up-regulated levels of TCR and CD69 molecules) depends on further interactions with MHC molecules and, if so, whether such interactions are required for survival, for maturation, or for both. The involvement of the TCR and/or CD4/CD8 coreceptors in transmitting additional signals is also unknown. We have examined these questions by analyzing survival and differentiation of early (CD4 + CD8 + TCR hi) and later (CD4-CD8 + TCR. hi) postselection stages of thymocytes from normal and bcl-2 transgenic mice expressing transgenic, class I MHC-restricted TCR, upon intrathymic transfer into recipients that lacked ligands either for both the TCR and CD8 coreceptor, or for the TCR only. The results provide direct evidence that induction of differentiation of CD4+CD8 + thymocytes by recognition of MHC molecules does not rescue them from PCD and is insufficient to activate the entire maturation program. Both processes require continual engagement of the TCR by positively selecting MHC molecules that, at least in the case of class I MHC-restricted CD4-CD8 + T cells, cannot be substituted by the engagement of coreceptor alone.

Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection

“…On the other hand, positively selecting low-affinity/avidity ligands may achieve sustained signaling by their inability to induce maximal TCR internalization and the TCR complexes that remain on the surface are able to relay continuous signals for survival and differentiation. This is consistent with observations from other models that show that multiple interactions are required to promote thymocyte differentiation (43,44). The current literature supports the role of ERK in positive selection (5-9, 11, 12) and other reports show that sustained ERK signals are observed during positive selection (10,13).…”

Maturational stage-dependent thymocyte responses to TCR engagement

“…Experiments using intrathymic transfer and re-aggregation cultures indicated that sustained interactions with the thymic stroma are required for completion of positive selection [19,20]. Hare et al [43] found that completion of development with the thymic stroma was MHC independent.…”

“…The progression from immature TCR low CD4 + CD8 + DP thymocytes to fully functional TCR high CD4 -CD8 + or TCR high CD4 + CD8 -SP thymocytes requires sustained TCR-mediated signaling events [19,20], and is characterized by distinct maturational stages, defined by cell surface markers [21][22][23]. It has been shown that DP thymocytes can be positively selected by low-avidity interactions [24].…”

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

“…It is unclear, however, how purely quantitative differences in TCR signaling could lead to the tight association that is normally seen between MHC-I vs MHC-II recognition and CD4/CD8-lineage commitment. Given that positive selection is a relatively prolonged process (16,17), it seems likely that additional steps during positive selection reinforce the initial signaling differences to ensure that developing T cells choose the lineage appropriate to their TCR specificity (reviewed in Refs. 18 and 19).…”