How αβ T cells deal with induced TCRα ablation

Polić, Bojan; Kunkel, Désirée; Scheffold, Alexander; Rajewsky, Klaus

doi:10.1073/pnas.141218898

Cited by 209 publications

(208 citation statements)

References 36 publications

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“…This implies, with respect to the reported kinetics of BFL1/A1 expression with return to basal levels at about 48 h after TCR stimulation [22], that at least a fraction of the CD31 -central naive T cells have recently been stimulated via their TCR. The observation that in all samples analyzed BFL-1/A1 expression was not enhanced in CD45RO + memory as compared to CD31 -central naive CD4 + T cells is consistent with the observation that memory CD4 + T cell maintenance is independent of MHC-II [28][29][30][31]. On the other hand the inconsistent up- regulation of BFL-1/A1 in memory as compared to CD31 + thymic naive CD4 + T cells could easily be explained by varying numbers of cells that have recently been activated in the course of foreign antigen encounter.…”

Section: Discussionsupporting

confidence: 89%

Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults

et al. 2005

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In spite of thymic involution early in life, the numbers of naive CD4 + T cells only slowly decline in ageing humans implying peripheral post-thymic naive CD4 + T cell expansion. This proliferation may compensate for continuous activation and death of naive CD4 + T cells but may also have negative consequences for protective immunity. Here we show that naive CD4 + T cells that have proliferated in the periphery are characterized by a highly restricted oligoclonal TCR repertoire. Additionally these cells, which constitute the majority of naive CD4 + T cells in the elderly, display signatures of recent TCR engagement. Our results demonstrate for the first time that peripheral post-thymic proliferation of naive CD4 + T cells in healthy human individuals causes a significant contraction of the peripheral TCR repertoire. This age-dependent deterioration of CD4 + T cell immunity could entail ageing-associated autoimmunity, increased susceptibility to infection or cancer and decreased efficiency of vaccination.

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Section: Discussionsupporting

confidence: 89%

Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults

et al. 2005

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“…IL-7 is arguably the most important cytokine for T-cell survival. In the present study, we found that F5 T cells have a half life of only 14 days in vivo in the absence of continued IL-7Ra expression, which is shorter than is observed in the absence of TCR signalling [33][34][35]. Interestingly, we found that F5 TCR transgenic T cells exhibited highly distinct survival profiles depending on the host environment they came from.…”

Section: Il-7 Signalling In Vivo Regulates Mitochondrial Homeostasismentioning

confidence: 40%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

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The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Ra, we show that T-cell longevity in the absence of survival cues is not a cellintrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Ra expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is nonlimiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.Key words: Fitness . Homeostasis . IL-7 . T cells Supporting Information available onlineIntroduction A commonly evoked concept in studies of lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state, or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness [1]. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of 9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.Ã These authors contributed equally to this work. 3656The mechanisms by which IL-7 maintains T-cell survival, and therefore regulate cellular fitness, have been the subject of numerous studies. Many of these have focused on the transc...

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“…For CD8 + memory T cells, the situation is less clear. Their numbers decline upon ablation of their TCR 98. CD8 + memory T cells not expressing CD122 do, but CD122 expressing cells do not require MHC class I 100, 101, 102.…”

Section: The Lifestyle Of Circulating Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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How αβ T cells deal with induced TCRα ablation

Cited by 209 publications

References 36 publications

Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults

Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Immunological memories of the bone marrow

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