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Naive CD4+ T cells are more resistant to age-related loss than naive CD8+ T cells, suggesting mechanisms that preferentially protect naive CD4+ T cells during aging. Here, we show that TRIB2 is more abundant in naive CD4+ than CD8+ T cells and counteracts quiescence exit by suppressing AKT activation. TRIB2 deficiency increases AKT activity and accelerates proliferation and differentiation in response to interleukin-7 (IL-7) in humans and during lymphopenia in mice. TRIB2 transcription is controlled by the lineage-determining transcription factors ThPOK and RUNX3. Ablation of Zbtb7b (encoding ThPOK) and Cbfb (obligatory RUNT cofactor) attenuates the difference in lymphopenia-induced proliferation between naive CD4+ and CD8+ cells. In older adults, ThPOK and TRIB2 expression wanes in naive CD4+ T cells, causing loss of naivety. These findings assign TRIB2 a key role in regulating T cell homeostasis and provide a model to explain the lesser resilience of CD8+ T cells to undergo changes with age. [Display omitted] • Expression of TRIB2 is higher in naive CD4+ than naive CD8+ T cells • TRIB2 transcription is upregulated by ThPOK and inhibited by RUNX3 • TRIB2 in CD4+ T cells inhibits AKT activation in response to homeostatic cytokines • TRIB2 deficiency in CD8+ T cells enhances their proliferation and differentiation Naive CD4+ and CD8+ T cells differ in homeostatic proliferation, which may explain the higher loss of naive CD8+ cells during human aging. Here, Cao et al. describe that TRIB2 , regulated by ThPOK and RUNX3, protects naive CD4+ T cells from untimely quiescence exit and loss of naivety. [ABSTRACT FROM AUTHOR]

Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological "layer" of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid cells, myeloid cells, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity-with a substantial degree of inter-individual variation at the time of birth-rather than via a transition between discrete waves. These findings have important implications for the design of strategies for prophylaxis against infection in the newborn and for the use of umbilical cord blood (UCB) in the setting of transplantation., Competing Interests: Declaration of Interests C.J.Y. declares partnership at Related Sciences and TReX Bio and owns stock in DroPrint Genomics and Related Sciences. C.J.Y. is supported by research grants from CZ Biohub, CZI, and PICI., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Summary The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing β5t, we showed that aberrant expression of self-peptides generated by β5t affects CD8+ T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8+ T cells. In mice in which β5t was expressed both in cortical and medullary TECs, the abundance of CD8+ lineage thymocytes was reduced, and extra-thymic expression of β5t caused accumulation of CD8+ T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that β5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues. Graphical Abstract Highlights • Mice expressing β5t in both cTECs and mTECs show decreased CD8+ lineage thymocytes • Extra-thymic expression of β5t accumulates memory or exhausted CD8+ T cells • Extra-thymic expression of β5t causes autoreactive T cell responses in vivo Tomaru et al. show that aberrant expression of self-peptides generated by thymoproteasomes, which are expressed exclusively in the thymic cortex, affects CD8+ T cell homeostasis. Restricted expression of thymoproteasomes is crucial for thymic selection, maintenance of the peripheral naive pool of CD8+ T cells, and avoiding autoimmune responses. [ABSTRACT FROM AUTHOR]

The thymoproteasome subunit β5t is specifically expressed in cortical thymic epithelial cells (TECs) and generates unique peptides to support positive selection. In this study, using a mouse model ubiquitously expressing β5t, we showed that aberrant expression of self-peptides generated by β5t affects CD8 + T cell homeostasis, including thymic selection and maintenance of the peripheral naive pool of CD8 + T cells. In mice in which β5t was expressed both in cortical and medullary TECs, the abundance of CD8 + lineage thymocytes was reduced, and extra-thymic expression of β5t caused accumulation of CD8 + T cells with the memory or exhausted phenotype and induced autoreactive T cell responses. We found that thymoproteasomes are essential for positive selection but that the subsequent change in peptide repertoire in the medulla is also crucial for thymic selection and that β5t-derived peptide must be confined to the thymus to avoid autoimmunity in peripheral tissues., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)