T‐cell selection in the thymus: a spatial and temporal perspective

Abstract

Summary The ability of T cells to respond to a wide array of foreign antigens while avoiding reactivity to self is largely determined by cellular selection of developing T cells in the thymus. While a great deal is known about the cell types and molecules involved in T cell selection in the thymus, our understanding of the spatial and temporal aspects of this process remain relatively poorly understood. Thymocytes are highly motile within the thymus and travel between specialized microenvironments at different phases of their development while interacting with distinct sets of self-peptides and peptide presenting cells. A knowledge of when, where, and how thymocytes encounter self-peptide MHC ligands at different stages of thymic development is key to understanding T cell selection. In the past several years, our laboratory has investigated this topic using two-photon time-lapse microscopy to directly visualize thymocyte migration and signaling events, together with a living thymic slice preparation to provide a synchronized experimental model of T cell selection in situ. Here, we discuss recent advances in our understanding of the temporal and spatial aspects of T cell selection, highlighting our own work, and placing them in the context of work from other groups.

On certain two‐signal perspectives of lymphocyte activation and inactivation, thymic G‐quadruplexes, and the role of aggregation in self/not‐self discrimination

“…TdT was the first thymic enzyme to hint at localization of a function within the thymus; in this case, the generation‐of‐diversity function (abbreviated by Cohn as “GOD”) was in the cortex . In recent times, it has been recognized that the diverse cortical thymocytes, which have been positively selected, are “auditioned” in the thymic medulla . Here the product of the medulla‐specific Aire gene “promiscuously” expresses self‐antigens that negatively select (terminate) self‐reactive auditioners.…”

“…50 In recent times, it has been recognized that the diverse cortical thymocytes, which have been positively selected, are "auditioned" in the thymic medulla. 55 Here the product of the medulla-specific Aire gene "promiscuously" expresses self-antigens that negatively select (terminate) self-reactive auditioners. Intriguingly, it also emerged that Aire was expressed in another organ that shared with the thymus the triad of locally generated, individual-cell genetic diversity, promiscuous protein expression and massive cell death-the gonad.…”

Modulating the immune system through nanotechnology

“…During this process, thymic epithelial cells expose in their surface a great variety of self-antigens to T cells. Normally, the T cells that recognize those antigens are eliminated to prevent self-reactivity [244,245]. Besides central tolerance process, peripheral mechanisms regulate these self-reactive T cells if they reach the bloodstream.…”

Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice

“…By these processes, cells with a functional T-cell receptor (TCR) that is not autoreactive are allowed to survive. Maturation of DP thymocytes results in semi-mature intermediates (CD4 intermediates; Cibotti et al 1997; Kishimoto and Sprent 1997) that ultimately give rise to naïve CD4 + CD8 − or CD4 − CD8 + single positive (SP) thymocytes (Singer et al 2008; Hogquist et al 2015; Kurd and Robey 2016). Only a single study thus far (i.e., Brown et al 2006a) attempted to examine whether in addition to cell loss, differentiation of the DP population might be altered as well in DES-exposed animals.…”