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Interferons (IFNs) are a family of proteins that are generated in response to viral infection and induce an antiviral response in many cell types. The COVID-19 pandemic revealed that patients with inborn errors of type-I IFN immunity were more prone to severe infections, but also found that many patients with severe COVID-19 had anti-IFN autoantibodies that led to acquired defects in type-I IFN immunity. These findings revealed the previously unappreciated finding that central immune tolerance to IFN is essential to immune health. Further evidence has also highlighted the importance of IFN within the thymus and its impact on T-cell development. This review will highlight what is known of IFN's role in T-cell development, T-cell central tolerance, and the impact of IFN on the thymus. [ABSTRACT FROM AUTHOR]

Clonal deletion of T cells specific for self-antigens in the thymus has been widely studied, primarily by approaches that focus on a single receptor (using TCR transgenes) or a single specificity (using peptide-MHC tetramers). However, less is known about clonal deletion at the population level. In this article, we report an assay that measures cleaved caspase 3 to define clonal deletion at the population level. This assay distinguishes clonal deletion from apoptotic events caused by neglect and approximates the anatomic site of deletion using CCR7. This approach showed that 78% of clonal deletion events occur in the cortex in mice. Medullary deletion events were detected at both the semimature and mature stages, although mature events were associated with failed regulatory T cell induction. Using this assay, we showed that bone marrow-derived APC drive approximately half of deletion events at both stages. We also found that both cortical and medullary deletion rely heavily on CD28 costimulation. These findings demonstrate a useful strategy for studying clonal deletion within the polyclonal repertoire. [ABSTRACT FROM AUTHOR]

T cells can sometimes acquire properties of a memory cell without encountering foreign antigen. Miller et al. now show that development of such 'memory phenotype' (MP) CD8+ T cells starts with recognition of self-ligands in the thymus, and finishes in peripheral tissues. These cells respond rapidly during infection, and infiltrate tumors, where they express high amounts of PD-1. [ABSTRACT FROM AUTHOR]

We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic &brg;2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These pep-tide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive se-lection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this re-ceptor. One peptide tested, E1, induced positive selec-tion on the &brg;2M[-l-) background but negative selec-tion on the &brg;2M(+l-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy li-gands mediate positive selection. [ABSTRACT FROM AUTHOR]

Producing a healthy immune system capable of defending against pathogens, while avoiding autoimmunity, is dependent on thymic selection. Positive selection yields functional T cells that have the potential to recognize both self and foreign antigens. Therefore, negative selection exists to manage potentially self-reactive cells. Negative selection results from the induction of anergy, receptor editing, clonal diversion (agonist selection), and/or clonal deletion (apoptosis) in self-reactive clones. Clonal deletion has been inherently difficult to study because the cells of interest are undergoing apoptosis and being eliminated quickly. Furthermore, analysis of clonal deletion in humans has proved even more difficult due to availability of samples and lack of reagents. Mouse models have thus been instrumental in achieving our current understanding of central tolerance, and the evolution of elegant model systems has led to an explosion of new data to be assimilated. This review will focus on recent advances in the field of clonal deletion with respect to three aspects: the development of physiological model systems, signaling pathways that lead to apoptosis, and antigen presenting cell types involved in the induction of clonal deletion. [ABSTRACT FROM AUTHOR]

In the past few years, there has been a flurry of discoveries and advancements in our understanding of how the thymus prepares T cells to exist at peace in normal healthy tissue: that is, to be self-tolerant. In the thymus, one of the main mechanisms of T-cell central tolerance is clonal deletion, although the selection of regulatory T cells is also important and is gaining enormous interest. In this Review, we discuss the emerging consensus about which models of clonal deletion are most physiological, and we review recent data that define the molecular mechanisms of central tolerance. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The development of a self-tolerant and effective T cell receptor repertoire is dependent on interactions coordinated by various antigen presenting cells (APC) within the thymus. T cell receptor–self-peptide–MHC interactions are essential for determining T cell fate, however different cytokine and co-stimulatory signals provided by the diverse APCs within the thymus are also critical. Here, we outline the different localization and functional capabilities of thymic APCs. We also discuss how these distinct APCs work collectively to facilitate the establishment of a diverse T cell receptor repertoire that is tolerant to an array of different self-antigens. [ABSTRACT FROM AUTHOR]

Cortical thymic epithelial cells (cTECs) express a unique thymoproteasome subunit-β5T that plays an essential role in the development of CD8 T cells. In contrast, the immunoproteasome subunit-β5i is expressed in other thymic antigen-presenting cells (APCs). The thymoproteasome may generate peptides that are specialized for positive selection, or it may simply serve to generate peptides that are distinct from other APCs that cause negative selection, thereby promoting an overall larger number of surviving clones to mature and function in the immune system. To distinguish these models, we genetically engineered mice to express distinct peptide repertoires in cTECs vs. other APCs without expressing β5T, by generating β5t5i knockin mice, in which β5i-/- replaced β5T in cTECs. When such animals were crossed to β5i−/− mice, β5i was exclusively expressed in cTECs, whereas β5 was expressed in other cells. However, this mouse did not support normal positive selection, suggesting that β5T generates peptides that are intrinsically better for positive selection (i.e., β5i could not replace β5T) and not merely because these peptides are distinct from peptides presented by other APCs. Finally, using an Nur77GFP reporter, we show that the T cells generated in the absence of β5T have higher reactivity to self, generating predominantly CD44hi memory phenotype peripheral CD8+ T cells. Altogether, our results suggest that the thymoproteasome supports positive selection by generating peptides that are optimized for the selection of weakly self-reactive, naïve T-cell clones. [ABSTRACT FROM AUTHOR]

A prominent population of innate CD8+ T cells develops in the thymus of several gene-deficient mouse strains, including Itk, KLF2, CBP and Id3. These cells have the phenotype and function of memory CD8+ T cells, without previous exposure to antigen. Surprisingly, the cytokine IL-4 plays a key role in their development. As this developmental mechanism was discovered, it came to light that innate CD8+ T cells exist also in normal mice and in humans. In this review, we discuss how these cells develop, compare and contrast them to other CD8 memory cells, and discuss their potential physiological relevance. [Copyright &y& Elsevier]

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated. [ABSTRACT FROM AUTHOR]

A central tenet of T cell development postulates that if a developing thymocyte encounters self-antigen, it is induced to die via apoptosis, thereby protecting the organism from autoreactive T cells. We created transgenic mice that expressed a peptide antigen in the cortical epithelial cells of the thymus. This did not, however, result in deletion of specific T cells. Instead, antigen presentation by epithelial cells caused T cell receptor (TCR) internalization and increased gene rearrangement at the endogenous TCRα locus, or receptor editing. This editing mechanism in immature T cells parallels that which occurs in immature B cells, and has important implications for understanding positive and negative selection signaling in the thymus, and the limits of self-tolerance. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) is produced by a unique subset of invariant natural killer T (iNKT) cells (NKT2) in the thymus in the steady state, where it conditions CD8+ T cells to become "memory-like" among other effects. However, the signals that cause NKT2 cells to constitutively produce IL-4 remain poorly defined. Using histocytometry, we observed IL-4-producing NKT2 cells localized to the thymic medulla, suggesting that medullary signals might instruct NKT2 cells to produce IL-4. Moreover, NKT2 cells receive and require T cell receptor (TCR) stimulation for continuous IL-4 production in the steady state, since NKT2 cells lost IL-4 production when intrathymically transferred into CD1d-deficient recipients. In bone marrow chimeric recipients, only hematopoietic, not stromal, antigen-presenting cells (APCs), provided such stimulation. Furthermore, using different Cre-recombinase transgenic mouse strains to specifically target CD1d deficiency to various APCs, together with the use of diphtheria toxin receptor (DTR) transgenic mouse strains to deplete various APCs, we found that macrophages were the predominant cell to stimulate NKT2 IL-4 production. Thus, NKT2 cells appear to encounter and require different activating ligands for selection in the cortex and activation in the medulla. [ABSTRACT FROM AUTHOR]

Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77GFP transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim-/- mice had an increased number of GFPhi cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells. [ABSTRACT FROM AUTHOR]

Mammalian Kruppel-like transcription factors are implicated in regulating terminal differentiation of several tissue types. Deficiency in Kruppel-like factor (KLF) 2 (also known as LKLF) leads to a massive loss of the peripheral T-cell pool, suggesting KLF2 regulates T-cell quiescence and survival. Here we show, however, that KLF2 is essential for T-cell trafficking. KLF2-deficient (Klf2-/-) thymocytes show impaired expression of several receptors required for thymocyte emigration and peripheral trafficking, including the sphingosine-1-phosphate (S1P) receptor S1P1, CD62L and β7 integrin. Furthermore, KLF2 both binds and transactivates the promoter for S1P1—a receptor that is critical for thymocyte egress and recirculation through peripheral lymphoid organs. Our findings suggest that KLF2 serves to license mature T cells for trafficking from the thymus and recirculation through secondary lymphoid tissues. [ABSTRACT FROM AUTHOR]