Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells

Sakaguchi, Shimon; Sakaguchi, Noriko; Asano, Masanao; Itoh, Masae; Toda, Masaaki

doi:10.1038/ni.1840

Cited by 1,785 publications

(246 citation statements)

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“…Park et al (45) recently showed that RUNX3 is induced by common ␥ chain (␥c) receptor signaling during CD8 T specification. The process is dependent on STAT5 or STAT6 as ␥c-related cytokine stimulation of thymocytes from Stat5/6 double knock-out mouse did not induce Runx3 expression.…”

Section: Discussionmentioning

confidence: 99%

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

Lai

Mager

2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

Lai

Mager

2012

Journal of Biological Chemistry

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“…During positive selection, class II recognition is thought to induce strong persistent signaling that results in a cascade of transcriptional regulation by factors such as GATA3 and T-helper-inducing POZ/Krüppel-like factor, which results in fixation of cells to the CD4 lineage (3,4). In contrast, weaker or transient signaling by class I MHC results in the cytokine-dependent induction of a Runx3-mediated transcriptional program that induces CD8 lineage commitment (5)(6)(7)(8).…”

Section: Cd4 T Cells | Cd8 T Cellsmentioning

confidence: 99%

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

Sinclair

Bains

Yates

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

143

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It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis. CD4 T cells | CD8 T cellsD evelopment of CD4 and CD8 lineage cells from common thymic precursors is one of the most fundamental developmental processes in the adaptive immune system. The predominance of CD4 over CD8 T-cell populations in the periphery has been apparent since helper and cytotoxic T cells were first delineated more than 30 y ago (1), but the cause of this signature bias has remained obscure. A key contribution arises from the ratio in which CD4 and CD8 lineage T cells are generated by the thymus. Single-positive (SP) thymocytes exist in the thymus at ∼4:1, a ratio that is highly conserved across mouse strains and other species, suggesting that the developmental mechanisms involved are fundamental to the processes that give rise to mature T cells in the thymus. During thymocyte development, T-cell antigen receptor (TCR) genes undergo somatic rearrangements to generate a broad repertoire of TCR structures. Negative and positive selection of thymocytes results in the deletion of autoreactive thymocytes and ensures that class I and class II MHC reactivity is correlated with CD8 and CD4 lineage specification. The molecular mechanisms underpinning these processes are increasingly well understood. Although survival of thymocytes is regulated by expression of Bcl2 family members, up-regulation of the BH3-only family member Bim has been specifically implicated as a key event in negative selection of thymocytes (2). During positive selection, class II recognition is thought to induce strong persistent signaling that results in a cascade of transcriptional regulation by factors such as GATA3 and T-helper-inducing POZ/Krüppel-like factor, which results in fixation of cells to the CD4 lineage (3, 4). In contrast, weaker or transient signaling by class I MHC results in the cytokine-dependent induction of a Runx3-mediated transcriptional program that induces CD8 lineage commitment (5-8).Despit...

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“…47 The preferential expansion of CD8 + reverted T cells makes our X-SCID case unique and suggests a more important role for CD132-signaling in proliferation (homeostatic or antigen-driven) of CD8 + T cells as compared to CD4 + T cells. 48 The IL2RG gene reversion in the polyclonal CD8 + T-cell outgrowth did not result in complete recovery of all clinical symptoms demonstrating that rescue of CD8 + T cells alone is not sufficient for full restoration of immunity. …”

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confidence: 99%

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers

Leeuwen²,

Barendregt

et al. 2013

Haematologica

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Mutations in the common gamma chain (γ c , CD132, encoded by the IL2RG gene) can lead to B + T − NK − X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8 + T cells and increased over time. Only the revertant CD8 + T cells showed normal expression of CD132 and the various CD8 + T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ + T cells and differentiated CD4 + CD27 − effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8 + T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells. A reversion of an IL2RG mutation in combined immunodeficiency

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Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells

Cited by 1,785 publications

References 50 publications

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

Role of Runt-related Transcription Factor 3 (RUNX3) in Transcription Regulation of Natural Cytotoxicity Receptor 1 (NCR1/NKp46), an Activating Natural Killer (NK) Cell Receptor

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

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