Reinterpreting recent thymic emigrant function: defective or adaptive?

Cunningham, Cody A.; Helm, Eric Y.; Fink, Pamela J.

doi:10.1016/j.coi.2017.12.006

Cited by 36 publications

(34 citation statements)

References 51 publications

(63 reference statements)

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“…For the most part, the temporal shift could be ascribed to the proportion of RTEs among Tconv cell pools, since the biases could be recapitulated by purifying RTEs from adult mice. RTEs dominate the Tconv cell pool in infant mice since they take ∼3 wk to fully mature (Berzins et al, 1998;Boursalian et al, 2004;Cunningham et al, 2018). What, then, are the differences in Tconv cells that underlie the shift in potential?…”

Section: Discussionmentioning

confidence: 99%

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Pratama

Schnell

Mathis

et al. 2019

Journal of Experimental Medicine

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RORγ+ and Helios+ Treg cells in the colon are phenotypically and functionally distinct, but their origins and relationships are poorly understood. In monocolonized and normal mice, single-cell RNA-seq revealed sharing of TCR clonotypes between these Treg cell populations, potentially denoting a common progenitor. In a polyclonal Treg cell replacement system, naive conventional CD4+ (Tconv) cells, but not pre-existing tTregs, could differentiate into RORγ+ pTregs upon interaction with gut microbiota. A smaller proportion of Tconv cells converted into Helios+ pTreg cells, but these dominated when the Tconv cells originated from preweaning mice. T cells from infant mice were predominantly immature, insensitive to RORγ-inducing bacterial cues and to IL6, and showed evidence of higher TCR-transmitted signals, which are also characteristics of recent thymic emigrants (RTEs). Correspondingly, transfer of adult RTEs or Nur77high Tconv cells mainly yielded Helios+ pTreg cells, recapitulating the infant/adult difference. Thus, CD4+ Tconv cells can differentiate into both RORγ+ and Helios+ pTreg cells, providing a physiological adaptation of colonic Treg cells as a function of the age of the cell or of the individual.

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Section: Discussionmentioning

confidence: 99%

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Pratama

Schnell

Mathis

et al. 2019

Journal of Experimental Medicine

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“…Contrary to Burnet's suggestion and to earlier studies, the current view is that tolerogenic immune cell death is not complement‐mediated. However, under some circumstances (ie, with recent thymus emigrants) complement is involved . Irrespective of actual mechanism, there is general agreement that a major mode of tolerance induction is the deletion of potentially self‐reacting cells from populations of lymphocytes whose members differ from each other in their specificities for antigens.…”

Section: Self‐/not‐self‐discrimination: Two Signal Hypothesismentioning

confidence: 99%

“…However, under some circumstances (ie, with recent thymus emigrants) complement is involved. 23 Irrespective of actual mechanism, there is general agreement that a major mode of tolerance induction is the deletion of potentially self-reacting cells from populations of lymphocytes whose members differ from each other in their specificities for antigens. Assuming antigen dose as critical for distinguishing immune and tolerant responses, there is then the question as to how self-antigens can be registered by an organism as at high dosage and not-self-antigens as at low dosage?…”

Section: Discrimination: Two Signal Hypothesismentioning

confidence: 99%

Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

Forsdyke

2019

Scand J Immunol

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With the emergence of clonal selection ideas in the 1950s, the development of immune cell repertoires was seen to require the negative selection of self‐reacting cells, with surviving cells exhibiting a broad range of specificities. Thus, confronting a universe of not‐self‐antigens, a potential host organism spread its resources widely. In the 1960s, the two signal hypothesis showed how this might work. However, in the 1970s an affinity/avidity model further proposed that anticipating a pathogen strategy of exploiting “holes” in the repertoire created by negative selection, hosts should also positively select near‐self‐reacting cells. A microbe mutating an antigen from a form foreign to its host to a form resembling that host should prevail over host defences with respect to that antigen. By mutating a step towards host self, along the path from non‐self to self, it should come to dominate the microbe population. By progressive stepwise mutations, such microbes would become better adapted, to the detriment of their hosts. But they would lose this advantage if, as they mutated closer to host self, they encountered progressively stiffer host defences. Thus, as described in the affinity/avidity model, positive selection of lymphocytes for specificities that were very close to, but not quite, anti‐self (ie, “anti‐near‐self”) should be an important host adaptation. While positive selection affects both B and T cells, mechanisms are uncertain. Converging evidence from studies of lymphocyte activation, either polyclonally (with lectins as “antigen‐analogs”) or monoclonally (by specific antigen), supports the original generic affinity/avidity model for countering mutations towards host self.

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“…Previously, RTEs were considered functionally immature and simply "defective" versions of their mature counterparts. However, accumulating evidence suggests that RTEs could play an important role in maintaining immune tolerance (Cunningham et al 2018). However, in humans, studies on thymic function are limited due to the inaccessibility of the target organ and thus, much of the available information regarding functional characteristics of RTEs stems from animal models.…”

Section: Thymus-the Forgotten Organ Revisitedmentioning

confidence: 99%

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

Hellberg

2019

Linköping University Medical Dissertations

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Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a prerequisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement. The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4 + T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4 + T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment. The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4 + T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAK-STAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31

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Reinterpreting recent thymic emigrant function: defective or adaptive?

Cited by 36 publications

References 51 publications

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

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