The correlation between levels of IL-7Rα expression and responsiveness to IL-7 is lost in CD4 lymphocytes from HIV-infected patients
Colle, Jean-Hervéa; Moreau, Jean-Louisa; Fontanet, Arnaudb; Lambotte, Olivierc; Delfraissy, Jean-Françoisc; Thèze, Jacquesa
aUnité Immunogénétique Cellulaire, Département Infection et Epidémiologie
bUnité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France
cService de Médecine Interne, Hôpital de Bicêtre, Le Kremlin Bicêtre, France.
Received 19 June, 2006
Revised 1 September, 2006
Accepted 27 September, 2006
Measurements of Bcl-2 and CD25 expression suggested that IL-7R function is modified in CD4 lymphocytes of untreated viraemic patients. The extent of IL-7R function restoration post-HAART was analysed. A positive linear relationship was demonstrated between IL-7Rα expression and the magnitude of IL-7-induced responses in healthy individuals, whereas this relationship is lost in HIV-infected patients, suggesting that viraemic patients suffer a receptor signaling transduction defect in IL-7R function. IL-7 responsiveness is only partly restored by HAART.
IL-7 is a well-known lymphopoietic cytokine that plays a critical role in peripheral T-lymphocyte homeostasis. IL-7 is required both for the survival of naive T-cell populations and the homeostatic cycling of naive and memory cells . Plasma levels of IL-7 are increased in HIV-infected patients . These elevated levels may affect the CD4 cell count, and we have previously shown that HIV-infected patients with low IL-7 levels before the start of HAART have a diminished capacity for immune reconstitution . However, this rise in IL-7 levels does not prevent the CD4 cell count from falling during HIV infection. In addition, HIV infection may involve defects in the IL-7/IL-7R system. A decrease in IL-7Rα (CD127) expression was first reported to occur in CD8 T cells from HIV-infected patients . A similar trend was more recently reported for CD4 T cells . In addition, a further reduction in IL-7Rα expression in CD4 T cells was observed in individuals with advanced HIV disease. More recently, we demonstrated that IL-7R function is impaired in CD4 lymphocytes from untreated chronically HIV-infected patients, as measured by the reduced IL-7 induction of both the anti-apoptotic molecule Bcl-2 and the activation marker CD25 . In this report we focus our attention on whether or not the changes noted in the IL-7 responsiveness of CD4 T cells from HIV-infected patients are related to reduced levels of CD127 chain expression.
The relationship between CD127, Bcl-2 and CD25 expression was first examined in a control group of healthy individuals (Fig. 1). Mean fluorescence intensity (MFI) values for CD127-positive CD4 T cells were used to assess the level of CD127 expression. It was seen that surface levels of CD127 expression varied within the group (MFI median and quartiles values 162.8; 151.7–192.7). By contrast, the vast majority of CD4 T cells in the group were CD127 positive, and percentages of CD127-positive CD4 cells were very similar from one individual to another (96.7%; 96.1–97.3). We followed the IL-7-induced expression of Bcl-2 and CD25 by measuring the relative increases in their MFI in CD4 T cells stimulated in vitro. Spearman rank correlation coefficients showed that CD127 expression levels in healthy individuals were linearly correlated with IL-7-induced Bcl-2 and CD25 expression (r = 0.82, P < 0.004, r = 0.68, P < 0.03, respectively). This is therefore the first study to identify a positive linear association between the levels of IL-7Rα on the surface of CD4 T cells and the amplitude of the response induced by IL-7 in healthy individuals. Under normal physiological conditions, this feature may contribute to the mechanism underlying the biological effects of IL-7 because increasing the levels of CD127 would continuously modulate the magnitude of the IL-7 response. Moreover, under our experimental conditions, there is no evidence that the surface level of CD127 determines a threshold of reactivity in CD4 T cells. Consequently, the surface levels of CD127 can be predictive of IL-7 responses in healthy individuals.
We then further analysed the data obtained from two groups of HIV patients previously described . The group of untreated chronically infected patients was characterized by a plasma viral load of 17 100 RNA copies/ml (8900–26 700) and CD4 cell counts of 401 cells/μl (286–740) at enrollment. Briefly, as reported before, we noted in the patients a slightly lower percentage of CD127-positive CD4 cell percentage (88.3%; 87.2–89.4) and somewhat lower CD127 cell surface expression (MFI 95.7; 91.6–104.0) than in the healthy controls. A striking reduction was observed in IL-7-induced Bcl-2 and CD25 expression. The relative increase in Bcl-2 was reduced to 15.2% (10.3–20.0) of the values noted in the controls. The reduction in IL-7-induced CD25 expression was more moderate (54.9%; 45.4–63.5). Here we failed to detect any significant correlation between CD127 levels and the IL-7-induced responses in this group (Fig. 1), indicating that surface levels of CD127 did not account directly for the reduced IL-7 responses. Furthermore, in this group, the levels of IL-7-induced Bcl-2 and CD25 expression were clearly correlated (r = 0.75, P < 0.02 Spearman's test), indicating that the decrease in Bcl-2 and CD25 expression in this group had a similar source. IL-7 plasma levels were higher in the untreated group (16.2 pg/ml; 8.3–21.2) than in the control group (1.4 pg/ml). Given that IL-7 has the capacity to downregulate the expression of its own receptor , we investigated a possible correlation between the levels of CD127 expression and levels of IL-7 in the plasma. No statistically significant correlation was found (Spearman rank correlation test P > 0.05) making it unlikely that levels of circulating IL-7 have a direct effect on this parameter.
The data obtained from the group of patients who had been given HAART for at least one year were also analysed. Here the viral load was under control at 50 copies/ml plasma or less over the previous 6 months and immune restoration was evident with CD4 cell counts of 526 cells/μl (486–597). A slight decrease in the CD127-positive CD4 percentage (95.7%; 93.1–96.4) and in CD127 MFI (132.4; 113.0–141.2) was nevertheless observed. IL-7 stimulation in vitro increased Bcl-2 and CD25 (79.0%; 70.4–96.8) and 83.5% (74.9–93.7), respectively, relative to healthy controls. This is consistent with the fact that CD4 lymphocytes from HAART patients are more IL-7-responsive than those from untreated viraemic patients (see above). However, as shown (Fig. 1), the correlation between the surface levels of CD127 and IL-7-induced Bcl-2 expression was not restored, and the same was observed for CD25 expression. This indicates that the capacity of IL-7R to modulate CD4 T-cell responsiveness to IL-7, as seen in the controls, was not recovered in the HAART group.
Taken together, our results provide further insights into the mechanism by which T-cell homeostasis is disrupted during HIV disease. Our data obtained in untreated viraemic patients suggest that behind the reduction in CD127 expression, downstream of IL-7R, cellular defects may contribute to a decrease in IL-7 responsiveness. This defect may involve part of the IL-7R signal transduction pathway such as the Akt/phosphatidylinositol-3 kinase or the JaK/STAT pathway . The effect may also be related to cellular defects independent of the IL-7/IL-7R system. This would be in agreement with our previous work describing abnormalities in the IL-2 response of T lymphocytes from HIV-infected individuals [9,10], which were found to be associated with dysfunction of the JaK/STAT pathway, which is shared by the IL-2R and IL-7R systems . We have previously described that HAART partly restores IL-7-induced Bcl-2 and CD25 expression . The data presented here further suggest that altered IL-7 responsiveness somehow persists in HAART patients. This may have profound consequences on the partial immune response restoration generally observed with HAART, and should be taken into consideration when evaluating the therapeutic potential of IL-7.
The authors would like to thank Dr Thierry Rose, Olivier Juffroy, Simon Poter and Michel Morre for their helpful discussions and continuous support in the course of this work.
Sponsorship: This work was supported by Institut Pasteur, grants from the Agence Nationale de Recherche sur le SIDA (ANRS) and from Cytheris S.A.
1. Fry TJ, Mackall CL. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 2005; 174:6571–6576.
2. Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Leonore A, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med 2001; 7:73–79.
3. Beq S, Rannou M-T, Fontanet A, Delfraissy J-F, Thèze J, Colle JH. HIV infection: pre-highly active antiretroviral therapy IL-7 plasma levels correlate with long-term CD4 cell count increase after treatment. AIDS 2004; 18:563–565.
4. MacPherson PA, Fex C, Sanchez-Dardon J, Hawley-Foss N, Angel JB. Interleukin-7 receptor expression on CD8(+) T cells is reduced in HIV infection and partially restored with effective antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 28:454–457.
5. Paiardini M, Cervasi B, Albrecht H, Muthukumar A, Dunham R, Gordon S, et al. Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J Immunol 2005; 174:2900–2909.
6. Colle JH, Moreau JL, Fontanet A, Lambotte O, Joussemet M, Jacod S, et al. Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients – effects of antiretroviral therapy. J Acquir Immune Defic Syndr 2006; 42:277–285.
7. Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 2004; 21:289–302.
8. Jiang Q, Li WQ, Aiello FB, Mazzucchelli R, Asefa B, Khaled AR, et al. Cell biology of IL-7, a key lymphotrophin. Cytokine Growth Factor Rev 2005; 16:13–33.
9. David D, Bani L, Moreau JL, Treilhou MP, Nakarai T, Joussemet M, et al. Regulatory dysfunction of the interleukin-2 receptor during HIV infection and the impact of triple combination therapy. Proc Natl Acad Sci USA 1998; 95:11348–11353.
10. Kryworuchko M, Pasquier V, Keller H, David D, Goujard C, Gilquin J, et al. Defective interleukin-2-dependent STAT5 signalling in CD8 T lymphocytes from HIV-positive patients: restoration by antiretroviral therapy. AIDS 2004; 18:421–426.
This article has been cited 13 time(s).
Plos OneDecreased IL-7 Responsiveness Is Related to Oxidative Stress in HIV DiseasePlos One
Journal of Biological ChemistryMembrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cellsJournal of Biological Chemistry
Journal of VirologyInterleukin-7 enhances proliferation responses to T-cell receptor stimulation in naive CD4(+) T cells from human immunodeficiency virus-infected personsJournal of Virology
Journal of ImmunologyIdentification and Biochemical Characterization of Human Plasma Soluble IL-7R: Lower Concentrations in HIV-1-Infected PatientsJournal of Immunology
Journal of Infectious DiseasesDown-Regulation of Interleukin-7 Receptor (CD127) in HIV Infection Is Associated with T Cell Activation and Is a Main Factor Influencing Restoration of CD4(+) Cells after Antiretroviral TherapyJournal of Infectious Diseases
CytokineDisruption of the gamma c cytokine network in T cells during HIV infectionCytokine
Journal of Biological ChemistryInterleukin-7 Compartmentalizes Its Receptor Signaling Complex to Initiate CD4 T Lymphocyte ResponseJournal of Biological Chemistry
Plos OneDevelopment of a Quantitative Bead Capture Assay for Soluble IL-7 Receptor Alpha in Human PlasmaPlos One
Journal of VirologyDual Mechanism of Impairment of Interleukin-7 (IL-7) Responses in Human Immunodeficiency Virus Infection: Decreased IL-7 Binding and Abnormal Activation of the JAK/STAT5 PathwayJournal of Virology
Journal of Biological Regulators and Homeostatic Agents
Glucocorticoids Upregulate Decreased Il-7 Receptor Expression in Asthmatic Patients and Simian Immunodeficiency Virus-Infected Non-Human Primates
Journal of Biological Regulators and Homeostatic Agents, 27(2):
AIDS Research and Human RetrovirusesNuclear JAK3 and Its Involvement in CD4 Activation in HIV-Infected PatientsAIDS Research and Human Retroviruses
© 2007 Lippincott Williams & Wilkins, Inc.