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T Petteri Arstila

Publications and source records attributed to T Petteri Arstila.

7 recordsLinked to original sources
PubMed2007

A defect of regulatory T cells in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire(-/-) mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire(-/-) mice, in the patients a key mediator of active tolerance, the CD4(+)CD25(+) regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE(+) cells was seen around thymic Hassall's corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire(-/-) mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.

Adult↗
PubMed2006

Most human thymic and peripheral-blood CD4+ CD25+ regulatory T cells express 2 T-cell receptors.

Lack of allelic exclusion in the T-cell receptor (TCR) alpha locus gives rise to 2 different TCRs in 10% to 30% of all mature T cells, but the significance of such dual specificity remains controversial. Here we show that human CD4+ CD25+ regulatory T (Treg) cells express 2 distinct Valpha chains and thus 2 TCRs at least 3 times as often as other T cells. Extrapolating from flow cytometric analysis using Valpha2-, Valpha12-, and Valpha24-specific monoclonal antibodies (mAbs), we estimated that between 50% and 99% of the CD25+ Treg cells were dual specific, as compared with about 20% of their CD25- counterparts. Moreover, both TCRs were equally capable of transmitting signals upon ligation. Cells with 2 TCRs also expressed more FOXP3, the Treg-cell lineage specification factor, than cells with a single TCR. Our findings suggest that expression of 2 TCRs favors differentiation to the Treg-cell lineage in humans and raise the question of the potential functional consequences of dual specificity.

Adult↗
PubMed2006

Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

Animals↗
PubMed2003

The repertoires of circulating human CD8(+) central and effector memory T cell subsets are largely distinct.

Memory T cells are divided into central and effector subsets with distinct functions and homing capabilities. We analyzed the composition and dynamics of the CD8(+) T cell repertoire of these subsets within the peripheral blood of four healthy individuals. Both subsets had largely distinct and autonomous TCRbeta repertoires. Their composition remained stable over a 9 month period, during which no cell passage between these subsets was detected despite important size variation of several clones. In one donor, four out of six TCRbeta clonotypes specific for the influenza A virus were detected in the central subset only, while the two others were shared. Altogether, these observations suggest that most effector memory T cells may not have derived from the central memory subset.

Adult↗
PubMed2002

Long-lived memory T lymphocyte responses after hantavirus infection.

Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome (HFRS), which is an important public health problem in large parts of Europe. We examined the memory cytolytic T lymphocyte (CTL) responses in 13 Finnish individuals who had HFRS between 1984 and 1995. In seven of these donors, we detected virus-specific CTL responses against the PUUV nucleocapsid (N) protein after in vitro stimulation with PUUV. Six novel CD8(+) CTL epitopes were defined on the N protein and were found to be restricted by various HLA alleles including A2, A28, B7, and B8. This is the first demonstration of PUUV-specific CTL responses in humans, and the first identification of CTL epitopes on PUUV. In addition, this study provides one of the few characterizations of a human antiviral memory T cell response, without the complicating issues of virus persistence or reinfection. Interferon (IFN)-gamma ELISPOT analysis showed that memory CTL specific for these epitopes were present at high frequency in PUUV-immune individuals many years after acute infection in the absence of detectable viral RNA. The frequencies of PUUV-specific CTL were comparable to or exceeded those found in other viral systems including influenza, EBV and HIV, in which CTL responses may be boosted by periodic reinfection or virus persistence.

Amino Acid Sequence↗
PubMed1995

Intraembryonic haemopoietic cells and early T cell development.

T cell precursors in the chick embryo have been localized into the intraembryonic mesenchyme (IEM) and into the para-aortic region before the first wave of the thymic colonization on embryonic day (ED) 6,5-8. The cell surface markers of avian prethymic stem cells are not known. It is also not known whether these precursor cells are already committed to the T cell lineage before their thymic colonization. In 7-day-old chick embryos Ov+ cells were found in the para-aortic region. Also the endothelial cells of the embryonic dorsal aorta were positively stained. Ov antigen might represent a very primitive marker for precursor cells having the potentiality to differentiate both to haemopoietic and endothelial cells. Scattered CD45+ cells were observed in the same para-aortic area as in many haemopoietic areas in the loose embryonic mesenchymal tissues. CD8 alpha (MoAb 3-298) expressing haemopoietic cells were detected before thymic colonization on ED6. In flow cytometric analysis of IEM precursors Ov, CD45 and CD8 alpha expressing cells seemed to form distinct subsets suggesting heterogeneity of these haemopoietic cells.

Animals↗