Quantification of thymic function by measuring T cell receptor excision circles within peripheral blood and lymphoid tissues in monkeys

125

The human thymus exports newly generated T cells to the periphery. As no markers have been identified for these recent thymic emigrants (RTE), it is presently impossible to measure human thymic output. T cell receptor excision circles (TREC) have been recently used to assess thymic output during both health and disease. Using a mathematical model, we quantify age-dependent changes both in the number of RTE generated per day and in TREC concentration during an 80-year lifespan. Through analyses, we demonstrate that RTE and peripheral T cell division have the same potential to affect TREC concentration at any age in healthy people. T cell death also influences TREC concentration, but to a lesser extent. During aging, our results indicate that thymic involution primarily induces an age-dependent decline in TREC concentrations within both CD4+ and CD8+ T cell populations. We further apply this model for studying TREC concentration during HIV-1 infection. Our analyses reveal that a decrease in thymic output is the major contributor to the decline in TREC concentration within CD4+ T cells, whereas both increased peripheral T cell division and decreased thymic output induce the decline in TREC concentration within CD8+ T cells. Therefore, we suggest that T cell turnover should be examined together with TREC concentration as a measure of RTE. If peripheral T cell division remains relatively unchanged, then TREC concentration indeed reflects thymic output.

Section: Reevaluation Of T Cell Receptor Excision Circles As a Measurmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Human Trec Modelmentioning

confidence: 99%

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Reevaluation of T Cell Receptor Excision Circles as a Measure of Human Recent Thymic Emigrants

Kirschner

2002

125

“…TREC consist of fragments of DNA excised during rearrangement of TCR genes and hence TREC levels represent the function of the thymus. Thus, aged subjects with an atrophied thymus have a 20-fold decrease in levels of TREC compared with young subjects (22) and nonhuman primates subjected to thymectomy have a 40-fold decrease in the levels of TREC 1 year after the procedure (23,24). If the T cell compartment of recipients of cardiac transplants was restored by proliferation of residual T cells, a decrease in levels of TREC in these subjects would indicate a lack of thymic function.…”

Section: Thymic Function and Restoration Of The T Cell Compartmentmentioning

confidence: 99%

Effacing of the T Cell Compartment by Cardiac Transplantation in Infancy

Ogle

West

Driscoll

et al. 2006

For cardiac transplantation in infants, T cells are depleted and the thymus is removed. These manipulations should cause profound defects in the T cell compartment. To test this concept, 20 subjects who underwent cardiac transplantation in infancy and healthy age-matched subjects were studied. The number of T cells in the blood was nearly normal in all subjects 1–10 years after surgery. However, newly generated T cells were undetectable in 10 recipients and 10-fold less than controls in 10, suggesting absence of thymic function. TCRβ chain diversity, measured by a novel technique, was ∼100-fold lower than controls. T cell function, deduced from levels of human herpesvirus 7 and response to hepatitis B immunization, were notably impaired. Yet cardiac transplant recipients were generally free of opportunistic infections. Our findings demonstrate a novel approach to measuring lymphocyte diversity and suggest that understanding how these subjects resist infection could yield important insights into immune fitness.

“…In the steady state normal murine adult thymus, 1.7% of the TCR high CD4 ϩ CD8 Ϫ SP (CD4SP) and 5.2% of the TCR high CD4 Ϫ CD8 ϩ SP (CD8SP) incorporate the DNA precursor bromodeoxyuridine (BrdU) within 4 h (10). In previous studies, we found that SP thymocytes that are submitted to such proliferation (also suggested in monkeys (12)) are totally mature (CD24 Ϫ , Qa-2 high ), thus being more similar to recent thymic emigrants (RTEs) and peripheral T cells than to the bulk of thymic medullary SP TCR high cells. This proliferation concerns cells that recently matured in the thymus, and therefore excludes mature T cells reentering the thymus (10).…”

Section: Quantitative and Qualitative Adjustment Of Thymic T Cell Promentioning

confidence: 93%

Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes

Campion

Lucas

Dautigny

et al. 2002

In normal mice, single-positive thymocytes proliferate before being exported into the peripheral T cell pool. We measured the in vivo proliferation rates of mature thymocytes in several TCR transgenic mice. Different monoclonal TCR transgenic single-positive thymocytes proliferated at different rates in a given MHC context. Conversely, mature thymocytes expressing a given TCR, generated in mice of different MHC haplotypes, also showed different rates of proliferation. In p59fyn-deficient mice, the proliferation rate of mature thymocytes was diminished. Thus, premigrant thymocyte expansion is TCR mediated and depends on TCR affinity for self peptide/MHC ligands. In addition, we show that mature thymocyte expansion is clonotypic, increases the daily thymic T cell output, and modifies the TCR repertoire of newly produced T cells.