Characterization of the T Cell Receptor Repertoire in Patients with Common Variable Immunodeficiency: Oligoclonal Expansion of CD8+ T Cells

Serrano, Davide; Becker, Kai; Cunningham‐Rundles, Charlotte; Mayer, Lloyd

doi:10.1006/clim.2000.4941

Cited by 40 publications

(37 citation statements)

References 44 publications

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“…Similar oligoclonal repertoires were detected by CDR3 V␤ analysis of CD8 ϩ , but not CD4 ϩ T cell populations in two nude/SCID patients tested 6 years after BMT, suggesting a differential maintenance of CD4 ϩ and CD8 ϩ TCR repertoire complexity (37). The CD8 ϩ CD45RO ϩ cells may be Ag-specific effector T cells directed against Ags to which the individuals are exposed or they may represent regulatory T cells (25,38). The reason why the oligoclonality developed mainly in the CD8 ϩ T cell subset is unclear at the present time, although it has been previously reported in normal subjects (23).…”

Section: Figure 7 Cd8mentioning

confidence: 52%

“…ϩ CD45RO ϩ T cell subset of T cells, a phenomenon occurring with aging in the normal population (24,25). In addition, the partial loss of TCR diversity appeared to be due to CD8 ϩ T cell expansion in two patients (X-3 and X-6).…”

Section: Figure 7 Cd8mentioning

confidence: 99%

“…This phenomenon has been associated with aging and it may be a consequence of decreased thymic output and/or function (24,25). To determine whether the more skewed TCR repertoire observed 10 years after BMT (patients J-1 and X-3) or in patients that maintained a skewed repertoire beyond 1000 days of BMT (X-6: 52% oligoclonal and 48% polyclonal skewed V␤ profiles) resided in the CD8 ϩ CD45RO ϩ T cell subset, we separated T cell subsets by flow cytometric sorting and tested them by TCR immunoscope (Fig.…”

Section: Loss Of Tcr Diversity Is Due To An Expansion Of the Cd8 ϩ T mentioning

confidence: 99%

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T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation

Sarzotti¹,

Patel

Li³

et al. 2003

The Journal of Immunology

101

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Transplantation of HLA-identical or haploidentical T cell-depleted allogeneic bone marrow (BM) into SCID infants results in thymus-dependent T cell development in the recipients. Immunoscope analysis of the TCR Vβ repertoire was performed on 15 SCID patients given BM transplants. Before and within the first 100 days after bone marrow transplantation (BMT), patients’ PBMC displayed an oligoclonal or skewed T cell repertoire, low TCR excision circles (TREC) values, and a predominance of CD45RO+ T cells. In contrast, the presence of high numbers of CD45RA+ cells in the circulation of SCID patients >100 days post-BMT correlated with active T cell output by the thymus as revealed by high TREC values and a polyclonal T cell repertoire demonstrated by a Gaussian distribution of Vβ-specific peaks. Ten years after BMT, we observed a decrease of the normal polyclonal T cell repertoire and an increase of a more skewed T cell repertoire. A decline of TREC levels and a decrease in the number of CD45RA+ cells beyond 10 years after BMT was concomitant with the detection of oligoclonal CD3+CD8+CD45RO+ cells. The switch from a polyclonal to a more skewed repertoire, observed in the CD3+CD8+CD45RO+ T cell subset, is a phenomenon that occurs normally with decreased thymic output during aging, but not as rapidly as in this patient population. We conclude that a normal T cell repertoire develops in SCID patients as a result of thymic output and the repertoire remains highly diverse for the first 10 years after BMT. The TCR diversity positively correlates in these patients with TREC levels.

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Section: Figure 7 Cd8mentioning

confidence: 52%

Section: Figure 7 Cd8mentioning

confidence: 99%

Section: Loss Of Tcr Diversity Is Due To An Expansion Of the Cd8 ϩ T mentioning

confidence: 99%

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T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation

Sarzotti¹,

Patel

Li³

et al. 2003

The Journal of Immunology

101

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“…Because functional correlates of antigenic pMHCII/TCR interactions are distinct in mature T cells (activation, anergy) and developing thymocytes (positive and negative selection), one would expect phenotypic features reflecting both developmental stages. Indeed, a number of functional abnormalities has been observed in CVID, including restricted TCR repertoires (45,46), increased apoptosis (47-51), enhanced sensitivity of T cells to corticosteroids (47), an impairment of early signaling events triggered by TCR such as calcium flux, phospholipid metabolism and kinase activity (52)(53)(54), peripheral anergy, and dysregulation of the cytokine network including Th1 skewing (55,56). However, the nature of pMHC/ TCR interactions, particularly the longevity of pMHC/TCR complexes and kinetic thresholds between negative and positive selection, may fully account for many, if not all, abnormalities, including the modulation of Th1/Th2 differentiation (57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency

Královičová

Hammarström

Plebani

et al. 2003

The Journal of Immunology

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Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common primary immunodeficiencies in humans. A high degree of familial clustering, marked differences in the population prevalence among ethnic groups, association of IgAD and CVID in families, and a predominant inheritance pattern in multiple-case pedigrees have suggested a strong, shared genetic predisposition. Previous genetic linkage, case-control, and family-based association studies mapped an IgAD/CVID susceptibility locus, designated IGAD1, to the MHC, but its precise location within the MHC has been controversial. We have analyzed a sample of 101 multiple- and 110 single-case families using 36 markers at the IGAD1 candidate region and mapped homozygous stretches across the MHC shared by affected family members. Haplotype analysis, linkage disequilibrium, and homozygosity mapping indicated that HLA-DQ/DR is the major IGAD1 locus, strongly suggesting the autoimmune pathogenesis of IgAD/CVID. This is supported by the highest excess of allelic sharing at 6p in the genome-wide linkage analysis of 101 IgAD/CVID families using 383 marker loci, by previously reported restrictions of the T cell repertoires in CVID, the presence of autoantibodies, impaired T cell activation, and a dysregulation of a number of genes in the targeted immune system. IgAD/CVID may thus provide a useful model for the study of pathogenesis and novel therapeutic strategies in autoimmune diseases.

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“…The expansion of this lymphocyte population is also a hallmark of CVID patients with inflammatory diseases. These mechanisms could even provide an explanation for the inversion of the CD4/CD8 ratio, a well-known feature of a subset of CVID patients associated with autoimmunity and inflammation (66).…”

Section: Infections Inflammation and Autoimmunity In Cvidmentioning

confidence: 99%

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

Baldovino

Montin

Martino

et al. 2013

Autoimmunity Reviews

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Characterization of the T Cell Receptor Repertoire in Patients with Common Variable Immunodeficiency: Oligoclonal Expansion of CD8+ T Cells

Cited by 40 publications

References 44 publications

T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation

T Cell Repertoire Development in Humans with SCID After Nonablative Allogeneic Marrow Transplantation

Fine-Scale Mapping at IGAD1 and Genome-Wide Genetic Linkage Analysis Implicate HLA-DQ/DR as a Major Susceptibility Locus in Selective IgA Deficiency and Common Variable Immunodeficiency

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

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