Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

Deshpande, Neha; Parrish, Heather L.; Kuhns, Michael S.

doi:10.7554/elife.05949

Cited by 31 publications

(40 citation statements)

References 57 publications

(105 reference statements)

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“…Although in the young unmanipulated mice the majority of splenic CD4 + T cells have a naive phenotype, aged mice have more Ag-experienced T cells (Fig. 1C) (37). In line with an accumulation of Eomes + CD4 + cells after antigenic stimulation, unmanipulated aged mice (12-29 mo) showed a higher frequency of Eomes + CD4 + cells compared with young mice (1-3 mo) (Fig.…”

Section: Eomes + Cd4 + T Cells Accumulate With Agesupporting

confidence: 55%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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Section: Eomes + Cd4 + T Cells Accumulate With Agesupporting

confidence: 55%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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“…Some clones may be just too infrequent in older individuals to provide a meaningful response to immune challenge, while expanded ones may confer increased responsiveness to specific challenges. Moreover, some of these clones selected during homeostatic proliferation may have a higher affinity to self and therefore promote autoreactive immunity in the elderly (Deshpande et al, 2015; Goronzy and Weyand, 2012; Quinn et al, 2016). …”

Section: Age and The Naive T Cell Receptor Repertoire: How Much Divermentioning

confidence: 99%

Successful and Maladaptive T Cell Aging

2017

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Throughout life, the T cell system adapts to shifting resources and demands, resulting in a fundamentally restructured immune system in older individuals. Here we review the cellular and molecular features of an aged immune system and discuss the trade-offs inherent to these adaptive mechanisms. Processes include homeostatic proliferation that maintains compartment size at the expense of partial loss in stemness and incomplete differentiation and the activation of negative regulatory programs, which constrain effector T cell expansion and prevent increasing oligoclonality but also interfere with memory cell generation. We propose that immune failure occurs when adaptive strategies developed by the aging T cell system fail and also discuss how, in some settings, the programs associated with T cell aging culminates in a maladaptive response that directly contributes to chronic inflammatory disease.

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“…For example, positive and negative selection (von Boehmer & Melchers, ; Klein et al, ) remove non‐functional or potentially self‐reactive clones, and the initiation of lymphocyte responses is under the control of innate components of immunity (Iwasaki & Medzhitov, ) that can efficiently restrict these responses to ‘dangerous’ antigens. However, the long‐term evolution of lymphocytes can circumvent these ‘rules’, and give rise to lymphocytes with increased cross‐reactivity or auto‐reactivity (Deshpande, Parrish & Kuhns, ). Therefore, mechanisms of control have evolved also to constrain the scope of ‘selfish’ evolution: e.g.…”

Section: The Makings Of a Major Evolutionary Transitionmentioning

confidence: 99%

An evolutionary perspective on the systems of adaptive immunity

et al. 2017

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We propose an evolutionary perspective to classify and characterize the diverse systems of adaptive immunity that have been discovered across all major domains of life. We put forward a new function-based classification according to the way information is acquired by the immune systems: Darwinian immunity (currently known from, but not necessarily limited to, vertebrates) relies on the Darwinian process of clonal selection to 'learn' by cumulative trial-and-error feedback; Lamarckian immunity uses templated targeting (guided adaptation) to internalize heritable information on potential threats; finally, shotgun immunity operates through somatic mechanisms of variable targeting without feedback.We argue that the origin of Darwinian (but not Lamarckian or shotgun) immunity represents a radical innovation in the evolution of individuality and complexity, and propose to add it to the list of major evolutionary transitions. While transitions to higher-level units entail the suppression of selection at lower levels, Darwinian immunity re-opens cell-level selection within the multicellular organism, under the control of mechanisms that direct, rather than suppress, cell-level evolution for the benefit of the individual. From a conceptual point of view, the origin of Darwinian immunity can be regarded as the most radical transition in the history of life, in which evolution by natural selection has literally re-invented itself. Furthermore, the combination of clonal selection and somatic receptor diversity enabled a transition from limited to practically unlimited capacity to store information about the antigenic environment. The origin of Darwinian immunity therefore comprises both a transition in individuality and the emergence of a new information system -the two hallmarks of major evolutionary transitions.Finally, we present an evolutionary scenario for the origin of Darwinian immunity in vertebrates. We propose a revival of the concept of the 'Big Bang' of vertebrate immunity, arguing that its origin involved a 'difficult' (i.e. low-probability) evolutionary transition that might have occurred only once, in a common ancestor of all vertebrates. In contrast to the original concept, we argue that the limiting innovation was not the generation of somatic diversity, but the regulatory circuitry needed for the safe operation of amplifiable immune responses with somatically acquired targeting. Regulatory complexity increased abruptly by genomic duplications at the root of the vertebrate lineage, creating a rare opportunity to establish such circuitry. We discuss the selection forces that might have acted at the origin of the transition, and in the subsequent stepwise evolution leading to the modern immune systems of extant vertebrates.

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Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

Cited by 31 publications

References 57 publications

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Successful and Maladaptive T Cell Aging

An evolutionary perspective on the systems of adaptive immunity

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