Growth hormone resurrects adult human thymus during HIV-1 infection

Abstract

In conditions of severe T cell depletion, such as HIV-1 infection, limited T cell production by the thymus can thwart the immune response, putting individuals at increased risk of infection with opportunistic pathogens. In this issue of the JCI, Napolitano et al. report, in a prospective, randomized study, that treatment of HIV-1-infected adults with growth hormone may reverse thymic atrophy, as reflected by increased de novo thymic T cell production accompanied by increased peripheral T cell production (see the related article beginning on page 1085). While the long-term immunological and clinical benefits of growth hormone treatment remain unclear, the data suggest a way in which to enhance thymopoiesis and peripheral T cell production in immunodeficient individuals.

Figure 1. Generation of TRECs.

During thymopoiesis, the genes encoding the variable and constant regions of the TCR-α chain are being rearranged. This is accompanied by the deletion of the interspersed TRD@ and the formation of an episomal DNA excision circle (TREC) which can be detected and quantified by PCR.

Figure 2. Elucidation of effects of rGH treatment on T cell and TREC dynamics in HIV-1–infected individuals.

Effects of GH on thymic output and T cell proliferation have been described. Combined interpretation of T cell and TREC dynamics can be used to determine whether these effects contribute to increased naive CD4⁺ T cell numbers after rGH treatment in HIV-1–infected individuals. The figure exemplifies T cell dynamics (percentage of naive CD4⁺ T cells within the peripheral PBMC pool and number of naive CD4⁺ T cells) and TREC dynamics (TREC numbers and percentage of TREC-containing cells within the naive CD4⁺ T cell and PBMC population) prior to GH treatment (A) and different possible scenarios following GH treatment (B–D). Prior to GH treatment (A), the thymic production of naive CD4⁺ T cells shown is 2, and these cells divide 1 time in the periphery. This results in 4 naive CD4⁺ T cells (gray), which in total contain 2 TRECs. In scenario B, rGH is shown to only affect thymic output (4 naive CD4⁺ T cells). In scenario C, rGH is shown to only affect peripheral CD4⁺ T cell production (these cells are shown to divide twice in the periphery). In their current study in this issue of the JCI, Napolitano et al. (13) show that in fact rGH administration to HAART-treated HIV-1–infected adults concurrently affects both thymic output and peripheral naive CD4⁺ T cell proliferation, as shown in scenario D. The resultant effects include increased thymic production of naive CD4⁺ T cells and TRECs, an increase in the percentage of naive CD4⁺ T cells and TRECs within the peripheral PBMC pool, but decreased TREC frequency within naive CD4⁺ T cells.