A normal T cell receptor beta CDR3 length distribution in patients with APECED

Niemi, Heikki J.; Laakso, Sini M.; Salminen, Jukka; Arstila, T. Petteri; Tuulasvaara, Anni

doi:10.1016/j.cellimm.2015.03.005

Cited by 9 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A further indication of abnormal thymic selection is the present finding of a significantly longer CDR3 in the patients' Tr NAIVE cells. No difference was found in the CDR3 length of Th cells, confirming an earlier analysis using spectratyping . Previous studies have shown that starting from the CD4 + CD8 + CD3 low thymocytes, CDR3 is progressively shortened throughout thymic maturation, and the process is thus likely to span both positive and negative selection .…”

Section: Discussionsupporting

confidence: 84%

“…Several studies in both mice and humans have shown that thymic selection leads to a significant shortening of the CDR3 length, with most of the change linked to MHCdependent positive selection [15][16][17]. In accordance with an earlier study [18], comparison of the average CDR3 length in Th subsets showed no significant difference between APS-1 patients and controls ( Fig. 5A and data shown).…”

Section: Analysis Of Cdr3 Length Distributionsupporting

confidence: 90%

“…Previous studies have shown that starting from the CD4 + CD8 + CD3 low thymocytes, CDR3 is progressively shortened throughout thymic maturation, and the process is thus likely to span both positive and negative selection [18]. The biggest decrease in CDR3 length takes place at the transition from CD4 + CD8 + CD3 low to CD4 + CD8 + CD3 high thymocytes, a maturational stage taking place in thymic cortex and coinciding with positive selection [18]. Mouse studies have also shown that the shortening is MHC dependent [15,29].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

et al. 2017

View full text Add to dashboard Cite

Mutations in the autoimmune regulator gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease autoimmune polyendocrine syndrome type 1 (APS-1). The patients also have a functional defect in the FOXP3 regulatory T cell population, but its origin is unclear. Here, we have used T cell receptor sequencing to analyse the clonal relationship of major CD4 T cell subsets in three patients and three healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity-determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS-1 patients is not different from that in healthy controls. Rather, the patients' naive regulatory T cells may have an intrinsic defect imprinted already in the thymus.

show abstract

Section: Discussionsupporting

confidence: 84%

Section: Analysis Of Cdr3 Length Distributionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

et al. 2017

View full text Add to dashboard Cite

show abstract

“…2a, P < 0.001 KS test). The length distributions of both chains were normally distributed (Shapiro-Wilk test, P < 0.001) as has been observed previously (Moss and Bell 1996;Ma et al 2016;Niemi et al 2015). The average lengths of the CDR3α and β chains were 11.6 ± 7.4 and 12.3 ± 5.5 amino acids, respectively.…”

Section: Influence Of Cdr3 Length On Immunodominancesupporting

confidence: 76%

Revealing factors determining immunodominant responses against dominant epitopes

2019

View full text Add to dashboard Cite

Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses.

show abstract

“…These autoreactive T cells incite tissue injury and provoke systemic inflammation. Alterations in TCR Vβ loci and increased Vβ5.1 repertoire have been reported in APECED patients (Kogawa et al, 2002; Niemi et al, 2015). Notably, Aire −/− mice only recapitulate part of phenotypes of APECED (Anderson et al, 2002; Ramsey et al, 2002).…”

Section: Introductionmentioning

confidence: 92%

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

Zhu

Willette-Brown

Song

et al. 2017

Cell Host & Microbe

View full text Add to dashboard Cite

SUMMARY Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell–driven autoimmune disease caused by impaired central tolerance, are susceptible to developing chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop phenotypes reminiscent of APECED, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the potential link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or depletion of autoreactive CD4 T cells rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Importantly, fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development.

show abstract

A normal T cell receptor beta CDR3 length distribution in patients with APECED

Cited by 9 publications

References 39 publications

Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment

Revealing factors determining immunodominant responses against dominant epitopes

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

Contact Info

Product

Resources

About