Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses

Mélique, Suzanne; Yang, Cui; Lesourne, Renaud

doi:10.1016/j.bj.2022.03.008

Cited by 10 publications

(8 citation statements)

References 83 publications

(211 reference statements)

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“…Additionally, we observed upregulation of genes involved in cholesterol biosynthesis, a process known to be important for betaherpesvirus replication and T cell function but less well studied for thymocyte development (74,126). We also noted downregulation of genes known to be essential for maturation of DN and DP cells, including Cd4, Cd8, Rag1, Rag2, Tcf7, Themis, Lat, Rorc, Lck, Zap70, Cd5, Cd27, CD28, Bcl11b, Tox, and genes in the PluriNetwork pathway that are involved in pluripotency and cell fate (42,50,54,102,(127)(128)(129)(130)(131)(132). The thymocyte-expressed molecule involved in selection (Themis) has been well characterized as a major player in the maturation and selection of thymocytes (128).…”

Section: Discussionmentioning

confidence: 97%

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

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IntroductionHerpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.MethodsIn the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study the tropism of MRV in the thymus and determine cellular processes in the thymus that were disrupted by neonatal MRV infection. We then utilized tropism data to establish a cell culture system.ResultsHerein, we describe how MRV alters the thymic transcriptome during acute neonatal infection. We found that MRV infection resulted in major shifts in inflammatory, differentiation and cell cycle pathways in the infected thymus. We also observed shifts in the relative number of specific cell populations. Moreover, utilizing expression of late viral transcripts as a proxy of viral replication, we identified the cellular tropism of MRV in the thymus. This approach demonstrated that double negative, double positive, and CD4 single positive thymocytes, as well as medullary thymic epithelial cells were infected by MRV in vivo. Finally, by applying pseudotime analysis to viral transcripts, which we refer to as “pseudokinetics,” we identified viral gene transcription patterns associated with specific cell types and infection status. We utilized this information to establish the first cell culture systems susceptible to MRV infection in vitro.ConclusionOur research provides the first complete picture of roseolovirus tropism in the thymus after neonatal infection. Additionally, we identified major transcriptomic alterations in cell populations in the thymus during acute neonatal MRV infection. These studies offer important insight into the early events that occur after neonatal MRV infection that disrupt central tolerance and promote autoimmune disease.

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Section: Discussionmentioning

confidence: 97%

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Belean,

Xue,

Cisneros

et al. 2024

Front. Immunol.

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“…Themis has been shown specifically to be involved in promoting positive selection: the maturation of single positive T (SPT) cells from double positive T (DPT) cells before migration out of the thymus [53][54][55][56][57][58] . We therefore hypothesized that, relative to other strains containing a B6 haplotype at Themis, CC027 would likely show defects in some aspects of their T-cell compartment.…”

Section: A B C Dmentioning

confidence: 99%

A mutation inThemiscontributes to peanut-induced oral anaphylaxis in CC027 mice

Risemberg,

Smeekens,

Cruz Cisneros

et al. 2023

Preprint

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BackgroundThe development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut- sensitized CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, unlike C3H/HeJ (C3H) mice.ObjectiveTo determine the genetic basis of orally-induced anaphylaxis to peanut in CC027 mice.MethodsA genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 and five additional CC strains.ResultsAnaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis, and 4% having severe anaphylaxis. A total of eight genetic loci were associated with variation in response to peanut challenge, six associated with anaphylaxis (temperature decrease) and two associated with peanut-specific IgE levels. There were two major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in theThemis(thymocyte-expressed molecule involved in selection) gene. Consistent withThemis’ described functions, we found that CC027 have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells.ConclusionOur results demonstrate a key role forThemisin the orally-reactive CC027 mouse model of peanut allergy.

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“…The research team highlights growth factor receptor-bound protein 2 (GRB2) as the most important binding partner of THEMIS in both thymocytes and peripheral T cells. GRB2 facilitates THEMIS interaction with SHP-1, and furthermore prevents proteasome-mediated degradation of THEMIS [ 28 ].…”

Section: Also In This Issuementioning

confidence: 99%

What makes tics tick? Insights into Tourette syndrome

Kattner¹

2022

Biomedical Journal

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Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses

Cited by 10 publications

References 83 publications

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

A mutation inThemiscontributes to peanut-induced oral anaphylaxis in CC027 mice

What makes tics tick? Insights into Tourette syndrome

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