Evidence for extrathymic T cell maturation after thymectomy in infancy

Torfadottir, H.; Freysdóttir, Jona; Skaftadóttir, I.; Haraldsson, Ásgeir; Sigfússon, Gunnlaugur; Ögmundsdóttir, Helga M.

doi:10.1111/j.1365-2249.2006.03139.x

Cited by 42 publications

(48 citation statements)

References 23 publications

(52 reference statements)

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“…Previous short-term surveys showed that thymectomized children have reduced CD4 + T cell and TCR excision circle numbers compared with age-matched controls (6)(7)(8)(9)(10). More recently, reduction of naive CD4 + T cell numbers and production in thymectomized patients was shown to correlate with chronological age and time since thymectomy (11).…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of PBMC samples from YATECs, taken an average of 2 decades after thymectomy, revealed clear alterations in the CD4 + T cell compartment (as expected from previous studies on CHD patients; ref. [6][7][8][9][10][11] as well as in the CD8 + T cell compartment. We found decreased CD4 + and CD8 + T cell counts in YATECs compared with age-matched controls, and even compared with middle-aged adult controls (Figure 2A).…”

Section: Introductionmentioning

confidence: 99%

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Evidence of premature immune aging in patients thymectomized during early childhood

Sauce¹,

Larsen²,

et al. 2009

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While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4 + and CD8 + T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence of premature immune aging in patients thymectomized during early childhood

Sauce¹,

Larsen²,

et al. 2009

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“…Thymectomy at an early age has been shown to result in reduced CD4 ϩ and CD8 ϩ T-cell numbers, largely due to reduced naive T-cell counts, in the first years after thymectomy. These changes in the T-cell pool at an early age occur without obvious clinical consequences, 14,19,20 although diminished responses to tick-borne encephalitis have been reported. 18 The long-term effects of thymectomy during early childhood on the composition of the T-cell compartment are less unequivocal.…”

Section: Introductionmentioning

confidence: 99%

Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?

Gent¹,

Schadenberg²,

Otto³

et al. 2011

Blood

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Thymectomy during early childhood is generally thought to have serious consequences for the establishment of the Tcell compartment. In the present study, we investigated the composition of the T-cell pool in the first 3 decades after thymectomy during infancy due to cardiac surgery. In the first 5 years after thymectomy, naive and total CD4 ؉ and CD8 ؉ T-cell numbers in the blood and T-cell receptor excision circle (TREC) levels in CD4 ؉ T cells were significantly lower than in healthy age-matched controls. In the first years after thymectomy, plasma IL-7 levels were significantly elevated and peripheral T-cell proliferation levels were increased by ϳ 2-fold. From 5 years after thymectomy onward, naive CD4 ؉ and CD8 ؉ T-cell counts and TRECs were within the normal range. Because TREC levels are expected to decline continuously in the absence of thymic output, we investigated whether normalization of the naive T-cell pool could be due to regeneration of thymic tissue. In the majority of individuals who had been thymectomized during infancy, thymic tissue could indeed be identified on magnetic resonance imaging scans. Whereas thymectomy has severe effects on the establishment of the naive T-cell compartment during early childhood, our data suggest that functional regrowth of thymic tissue can limit its effects in subsequent years. (Blood. 2011;118(3):627-634)

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“…31 Because patients with ADA-SCID show alterations in thymic function and architecture, 32 the increase in gd T cells observed in the GT group could be related to the slow recovery of the thymic activity, implying a disadvantage in the ab TCR rearrangement. Moreover, the expression of CD8aa, a marker associated with extrathymic differentiation, 33,34 was not different across the considered study groups, indicating that after GT, like BMT, the immune reconstitution process is mainly thymus derived.…”

Section: Discussionmentioning

confidence: 87%

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

Selleri

Brigida

Casiraghi

et al. 2011

Journal of Allergy and Clinical Immunology

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Background: Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies. Objectives: Limited information is available on the relative contribution of de novo thymopoiesis and peripheral expansion to T-cell reconstitution after GT as well as on the potential effects of gene transfer on hematopoietic stem cells and lymphocyte replicative lifespan. We studied these issues in patients affected by adenosine deaminase severe combined immune deficiency after low-intensity conditioning and reinfusion of retrovirally transduced autologous CD34 1 cells. Methods: Immunophenotype, proliferative status, telomere length, and T-cell receptor excision circles were investigated at early and late time points (up to 9 years) after GT treatment. Control groups consisted of pediatric healthy donors and patients undergoing allogeneic bone marrow transplantation (BMT). Results: We observed no telomere shortening in the bone marrow compartment and in granulocytes, whereas peripheral blood naive T cells from both GT and BMT patients showed a significant reduction in telomere length compared with healthy controls. This was in agreement with the presence of a high fraction of actively cycling naive and memory T cells and lower T-cell receptor excision circles. Conclusion: These data indicate that T-cell homeostatic expansion contributes substantially to immune reconstitution, like BMT, and is not associated with senescence in the stem cell compartment. (J Allergy Clin Immunol 2011;127:1368-75.)

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Evidence for extrathymic T cell maturation after thymectomy in infancy

Abstract: SummaryOur previous study showed that children who had been partially or completely thymectomized during heart surgery as infants had lower proportions and numbers of total lymphocytes and reduced proportions of T cells (CD3

Cited by 42 publications

References 23 publications

Evidence of premature immune aging in patients thymectomized during early childhood

Evidence of premature immune aging in patients thymectomized during early childhood

Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

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