Changes in thymic function with age and during the treatment of HIV infection

Abstract

The thymus represents the major site of the production and generation of T cells expressing αβ-type T-cell antigen receptors1. Age-related involution2 may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection3; this effect has been seen after chemotherapy and bone-marrow transplantation4,5. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells6,7. These cells could arise through expansion of existing naive T cells in the periphery8 or through thymic production of new naive T cells9,10. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.

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Figure 1: Generation of signal-joint and coding-joint TRECs and their detection in lymphocyte populations.
Figure 2: TREC levels in healthy, athymic and HIV-infected individuals.
Figure 3: Changes in signal-joint TREC levels after HAART.

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Acknowledgements

We thank J. Wong for monoclonal antibody 12F6; M. Gately for rhIL-2; F. Scott, J. McKinsey, A. Rahimi, S. Norris, G. Sempowski, J. Tomasch and M. Zupancic for sample collection and processing; A. Mobley and B. Darnell for FACS support; B. Dawson for viral load measurement; R.Scheuermann and D. Sodora for advice; and all the study participants for their cooperation. This work was supported by grants from the NIH and the American Foundation for AIDS Research. R.A.K., M.B.F. and J.A.Z. are Elizabeth Glaser Scientists of the Pediatric AIDS Foundation.

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Correspondence to Richard A. Koup.

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