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Contribution of CD4+, CD8+CD28+, and CD8+CD28- T Cells to CD3+ Lymphocyte Homeostasis During the Natural Course of HIV- 1 Infection

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Contribution of CD4+, CD8+CD28+, and CD8+CD28- T Cells to CD3+ Lymphocyte Homeostasis During the Natural Course of HIV- 1 Infection Contribution of CD4+, CD8+CD28+, and CD8+CD28- T cells to CD3+ lymphocyte homeostasis during the natural course of HIV- 1 infection. A Caruso, … , A Balsari, A Turano J Clin Invest. 1998;101(1):137-144. https://doi.org/10.1172/JCI195. Research Article The relationship between the number of circulating CD4+ T cells and the presence of particular CD8+ T cell subsets was analyzed by flow cytometry on PBL from asymptomatic HIV-1-infected patients whose specimens were collected every 2 mo for a total period of 32 mo. Only slight variations were detected in the absolute number of lymphocytes and percentage of CD3+ lymphocytes, whereas both CD4+ and CD8+ T cell subsets showed wide intrapatient variation. Variations in the number of CD8+CD28+ cells paralleled those of the CD4+ T cell subset in each patient tested, while the presence of CD8+CD28- T cells correlated inversely with CD4+ and CD8+CD28+ T cells. These data show that changes in the number of circulating CD4+-and CD8+CD28+ T cells are strongly related to the presence of CD8+CD28- T cells in these patients. Insight into the significance of CD8+CD28- T cell expansion will allow us to understand the mechanisms and significance of the HIV-1- driven change in CD4+CD8+ T cell homeostasis and the basic immunopathology of HIV disease. Find the latest version: https://jci.me/195/pdf Contribution of CD41, CD81CD281, and CD81CD282 T cells to CD31 Lymphocyte Homeostasis during the Natural Course of HIV-1 Infection A. Caruso,* S. Licenziati,* A.D. Canaris,* A. Cantalamessa,‡ S. Fiorentini,* S. Ausenda,* D. Ricotta,* F. Dima,* F. Malacarne,* A. Balsari,§ and A. Turano* *Institute of Microbiology, University of Brescia Medical School, Spedali Civili, 25123 Brescia, Italy; ‡Infectious Diseases Unit of Lovere, Ospedale Capitanio Gerosa, 24065 Lovere (Bergamo), Italy; and §Department of Immunology, University of Milan Medical School, 20133 Milan, Italy Abstract ized by chronic immune responses such as allograft rejection, graft-versus-host disease, and hemophilia (4, 5), or by the pres- The relationship between the number of circulating CD41 T ence of different viral infections such as cytomegalovirus cells and the presence of particular CD81 T cell subsets was (CMV),1 EBV, and influenza virus (6–8). The CD41/CD81 T analyzed by flow cytometry on PBL from asymptomatic cell ratio is evaluated routinely in HIV-1–seropositive (HIV1) HIV-1–infected patients whose specimens were collected ev- patients, who undergo a progressive loss of CD41 T cells and ery 2 mo for a total period of 32 mo. Only slight variations an increase in CD81 T cells. In an 8-yr follow-up of HIV1 indi- were detected in the absolute number of lymphocytes and viduals, Margolick et al. (9) showed that during the asymptom- percentage of CD31 lymphocytes, whereas both CD41 and atic stage of infection, a constant number of T cells is normally CD81 T cell subsets showed wide intrapatient variation. maintained without regard to CD41 or CD81 phenotype, Variations in the number of CD81CD281 cells paralleled termed blind T cell homeostasis. This phenomenon has also those of the CD41 T cell subset in each patient tested, while been observed in bone marrow transplant recipients (10). the presence of CD81CD282 T cells correlated inversely Since the increase in CD81 T cells in HIV1 patients is sus- with CD41 and CD81CD281 T cells. These data show tained by different subsets expressing surface markers such as that changes in the number of circulating CD41—and CD38, CD69, and HLA-DR (11–13), or lacking the CD28 sur- CD81CD281—T cells are strongly related to the presence of face marker (14–16), we asked whether a particular subset CD81CD282 T cells in these patients. Insight into the sig- might participate in blind T cell homeostasis or instead might nificance of CD81CD282 T cell expansion will allow us to be related to the presence of circulating CD41 T cells during understand the mechanisms and significance of the HIV-1– the natural course of HIV-1 infection. We analyzed CD41 T driven change in CD41/CD81 T cell homeostasis and the cells and CD81 T cell subsets in 10 asymptomatic HIV1 indi- basic immunopathology of HIV disease. (J. Clin. Invest. viduals whose blood samples were collected every 2 mo for a 1998. 101:137–144.) Key words: HIV • CD4 • CD28 • flow total of 32 mo. Our data show clearly that in the CD81 T cell cytometry • T cell subsets subsets evaluated, variations in the number of CD281 T cells matched variations in the number of CD41 T cells in each pa- Introduction tient tested. Moreover, CD31 T cell homeostasis was main- tained by the continuous production of CD81CD282 T cells. The two major subsets of circulating mature T lymphocytes, These findings raise the possibility that HIV-1–associated which express the CD4 and the CD8 cell surface markers, re- changes in the number of circulating CD41, CD81CD281, and spectively, can be divided further according to biological prop- CD81CD282 T cells are not random but strictly regulated, in- erties, expression of surface markers, and ability to produce dependent of their activation (CD381, CD691, and HLA- soluble factors such as cytokines and chemokines (1, 2). The DR1) status. genetic pattern of inheritance of the ratio between circulating 1 1 CD4 and CD8 T cells was studied recently in a population of Methods healthy donors and in randomly selected families; complex segregation analysis showed that a major recessive gene with a Patients and clinical evaluation. Ten HIV1 patients, two females polygenic component together with random environmental (M.N. and P.K.) and eight males (A.S., B.R., C.S., T.F., CH.M., V.G., factors control the CD41/CD81 T cell ratio in humans (3). Al- CH.S., and S.L.) all with a past history of intravenous drug abuse, though under genetic control, the CD41/CD81 ratio undergoes were selected at the Infectious Diseases Unit of Lovere from a cohort 1 profound alterations during many clinical situations character- of 112 HIV subjects. The inclusion criteria were positive HIV-1 ELISA, positive HIV-1 Western blot analysis, and negative hepatitis B virus, hepatitis C virus, HIV-2, and human T cell lymphotropic vi- rus–1/2 ELISA. All patients were asymptomatic (stage A) according Address correspondence to Prof. Arnaldo Caruso, Institute of Micro- to the 1993 classification system of the Centers for Disease Control biology, University of Brescia Medical School, Piazzale Spedali Civili, (17), and exhibited . 20% of all lymphocytes and $ 400 CD41 T 1, 25124 Brescia, Italy. Phone: 39-30-399-5859; FAX: 39-30-39-5258; cells/mm3 in peripheral blood. None of the patients received antiviral, E-mail: [email protected] antibiotic, or antimycotic treatment for the period of the study. Five Received for publication 21 March 1997 and accepted in revised patients stopped drug use 1–5 yr before enrollment, and five patients form 3 November 1997. were receiving methadone substitutive therapy. Blood samples were obtained from each patient every 2 mo for 32 mo. Control sub- J. Clin. Invest. jects were 50 age- and gender-matched healthy volunteers and 24 © The American Society for Clinical Investigation, Inc. 0021-9738/98/01/0137/08 $2.00 Volume 101, Number 1, January 1998, 137–144 1. Abbreviations used in this paper: CMV, cytomegalovirus; IEL, in- http://www.jci.org testinal intraepithelial lymphocytes; TCR, T cell receptor. T Lymphocyte Trends in HIV-1–seropositive Patients 137 Table I. Laboratory Findings for Subjects Studied Proportion of lymphocytes stained for Study group Lymphocytes CD3 CD4 CD8 CD4/CD8 absolute number/mm3 %% % % Healthy volunteers (n 5 50) 26806384 79.866.2 47.266.7 27.265.6 1.560.6 HIV2 subjects* (n 5 16) 28196761 74.065.1 47.062.5 27.665.4 1.760.4 HIV2 subjects‡ (n 5 8) 26376480 73.266.9 45.864.7 27.463.9 1.660.2 HIV1 subjects (n 5 10) 24306675 83.164.7 30.068.3 53.6610.1 0.660.3 Values are mean6SD. *Subjects with a past history of drug use. ‡Subjects with a past history of drug use and currently under methadone substitutive therapy. HIV-1–seronegative (HIV2) individuals who stated that they had ing was used to collect 10,000 events within the lymphocyte gate, been drug addicts until 6 mo–2 yr before entry in the study, 8 of defined as CD45bright with low side scatter (18). Data were analyzed whom were now receiving methadone substitutive therapy. The using Consort 32 and LYSYS II software. HIV2 individuals tested negative for hepatitis B and C virus, HIV-2, Statistics. Linear correlation coefficients were determined be- and human T cell lymphotropic virus–1/2 infection. Unlike the HIV1 tween the percentage or absolute number of CD41 T cells and the patients and healthy volunteers, the HIV2 individuals were moni- percentage or absolute number of CD81 T lymphocytes expressing tored for T cell subsets every 2–8 mo, with their consent. other surface antigens, namely CD28, CD38, CD69, and HLA-DR. A Blood processing and flow cytometry. Whole blood was obtained regression line was calculated by the least squares method, and corre- from overnight fasting patients and controls between 7:00 and 8:00 lation was defined as P . 0.5. Student’s t test was used to determine a.m., drawn in heparin-containing tubes, and processed for lympho- significance of differences. cyte count and subset evaluation after no more than 3 h from blood collection. The total number of lymphocytes was determined with a cell counter (Cell-Dyn 1700; Abbott Laboratories, North Chicago, Results IL).
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