Effects of exogenous interleukin-7 on human thymus function

Abstract

Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a ؉ CD3 ؊ CD4 ؉ CD8 ؉ stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3 ؊ cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-␣␤ rearrangement and indicate the potential use of IL-7 for enhancing de novo naïve T-cell generation in immunocompromised patients. ( IntroductionIt has been reported that T-cell numbers are maintained in adults predominantly through the expansion of postthymic, memory T cells, whereas in infants, T cells are predominantly maintained through the production of new naïve T cells by the thymus. 1 However, others and we have recently demonstrated that the adult thymus is still capable of thymopoiesis and can contribute to T-cell reconstitution in adults. 2,3 Several methods have been used to measure thymopoietic capacity. Thymic size as measured by radiographic imaging 1 and volumetric computed tomography measurements 4,5 have been correlated with numbers of CD4 ϩ CD45RA ϩ naïve T cells, and the number of phenotypically naïve T cells after transplantation has been shown to correlate with antigen-specific function. 6 However, there are concerns about limitations of estimating thymic function based on naïve T-cell phenotype alone. T cells expressing a naïve phenotype are not necessarily accurate surrogate markers of thymic function. Following thymic emigration, CD45RA ϩ naïve T cells can have a long quiescent life span, 7 may proliferate in an antigen-independent manner, 8 or may rapidly convert to CD45RO ϩ memory/effector phenotype T cells. 9 Furthermore, naïve T-cell markers may be acquired by memory T cells (especially CD8 ϩ T cells), 9,10 further compounding the difficulty in accurately enumerating naïve T cells. 11,12 To measure thymic function more directly in humans, we recently described an assay that quantifies an episomal DNA by-product of the T-cell receptor (TCR) rearrangement process. 2 These TCR rearrangement excision circles (TRECs) contain the ...

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

“…Notably, they include early thymocyte progenitors, including CD34 ϩ subpopulations, as well as more mature SP thymocytes. These results confirm previously published data from Okamoto et al (17), who showed that IL-7 treatment of human TOCs led to decreased apoptosis and increased intracellular Bcl-2 levels in immature CD3 Ϫ/low thymocytes and increased proliferation of SP thymocytes. In this report we extend these findings to show that CD34 ϩ thymocytes express high levels of surface IL-7R beginning at the CD34 high CD5 ϩ CD1a Ϫ stage of maturation and that this subpopulation is responsive to the anti-apoptotic and proliferative effects of IL-7.…”

“…IL-7-mediated up-regulation of Bcl-2 has been shown to promote the survival of murine and human T cells (5,17,18,40). Because over-expression of Bcl-2 abrogates glucocorticoid-induced apoptosis of murine thymocytes (41), we examined the effects of IL-7 on glucocorticoid (dexamethasone) treatment of human thymocytes.…”

“…Abs that block the function of IL-7 inhibit the in vitro differentiation of human CD34 ϩ progenitors derived from thymus or fetal liver to the CD4 ϩ CD3 Ϫ CD8 Ϫ (intrathymic T progenitor (ITTP) 4 cell, also termed "CD4 intermediate single-positive (ISP)") stage, suggesting that IL-7 is important to the survival of the ITTP (13,16). More recently, analysis of IL-7 effects on the survival of selected human thymocyte subpopulations showed that IL-7 enhances the survival of CD3 Ϫ/low thymocytes and increases TCR rearrangement (17). IL-7 also appears to facilitate the survival of positively selected CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in murine studies (18).…”

To kill or be killed: how HIV exhausts the immune system

“…In vitro, IL-7 provides potent antiapoptotic and proliferative signals to early thymocyte progenitors, mainly single positive 152 The contribution of IL-7 to thymic Tcell regeneration has been indicated by experiments using thymic organ culture systems, in which exogenous IL-7: (1) increased the frequency of TRECs in fetal, as well as infant, thymi, indicating that increased rearrangement of a TCRs had occurred; 153 (2) together with SDF-1, it enhanced the viability of CD34 þ T-cell precursors, by modulating the expression of Bcl-2 and Bax, and stimulated their proliferation. 153 In macaques infected with SIV, IL-7 induces both central renewal and a peripheral expansion of T lymphocytes associated with cell activation, without increasing the viral load. 154 However, comparison of pathogenic and nonpathogenic models of SIV infection showed that elevated levels of IL-7 are associated with disease progression.…”

Aging and T-cell diversity☆

“…Even naïve T cells are, therefore, present in identical replicates generated during and shortly after T-cell development in the thymus or in the periphery. Estimates of clonal sizes have come from the dilution of TRECs during thymic development (Douek et al, 1998;Okamoto et al, 2002). We have used TREC measurements in cord blood of babies born at different gestational ages (Schonland et al, 2003).…”