Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons

Background: Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8+ T cells represent an expanded, oligoclonal population. Methods: We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4+ and CD8+ T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8+ cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue. Results: Adipose tissue had a higher percentage of CD3+CD8+ T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8+HLA-DR+ T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8+CD57+ T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8+ T cells displayed distinct TCR&bgr; V and J gene usage, and the Shannon Entropy index, a measure of overall TCR&bgr; repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05). Conclusions: Adipose tissue is enriched for activated and late-differentiated CD8+ T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.

[1]  T. Sterling,et al.  Superior Glucose Tolerance and Metabolomic Profiles, Independent of Adiposity, in HIV-Infected Women Compared With Men on Antiretroviral Therapy , 2016, Medicine.

[2]  W. Baze,et al.  Infectious SIV resides in adipose tissue and induces metabolic defects in chronically infected rhesus macaques , 2016, Retrovirology.

[3]  M. Mohan,et al.  Adipose Tissue: Sanctuary for HIV/SIV Persistence and Replication. , 2015, Trends in microbiology.

[4]  Mikhail Pogorelyy,et al.  VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires , 2015, PLoS Comput. Biol..

[5]  S. Kalams,et al.  The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy , 2015, AIDS.

[6]  C. Rouzioux,et al.  Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection , 2015, PLoS pathogens.

[7]  E. Komech,et al.  tcR: an R package for T cell receptor repertoire advanced data analysis , 2015, BMC Bioinformatics.

[8]  Jeremy M. Brown,et al.  Human adipose tissue as a reservoir for memory CD4+ T cells and HIV , 2015, AIDS.

[9]  William S. DeWitt,et al.  Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection , 2015, Journal of Virology.

[10]  Chulhee Choi,et al.  Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction , 2014, Cellular and Molecular Immunology.

[11]  C. Bing,et al.  Interleukin-1β mediates macrophage-induced impairment of insulin signaling in human primary adipocytes , 2014, American journal of physiology. Endocrinology and metabolism.

[12]  M. Gerschenson,et al.  The Role of HIV and Monocytes/Macrophages in Adipose Tissue Biology , 2014, Journal of acquired immune deficiency syndromes.

[13]  F. Villarroya,et al.  Differentially Altered Molecular Signature of Visceral Adipose Tissue in HIV-1–Associated Lipodystrophy , 2013, Journal of acquired immune deficiency syndromes.

[14]  Patrice Duroux,et al.  IMGT/HighV QUEST paradigm for T cell receptor IMGT clonotype diversity and next generation repertoire immunoprofiling , 2013, Nature Communications.

[15]  R. Alexander,et al.  Clinical, Cosmetic and Investigational Dermatology Autologous Fat Grafting: Use of Closed Syringe Microcannula System for Enhanced Autologous Structural Grafting , 2022 .

[16]  Graham M Lord,et al.  Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet , 2013, Cell metabolism.

[17]  S. Mandard,et al.  Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors , 2013, PPAR research.

[18]  Bernard Keavney,et al.  High-Throughput 13-Parameter Immunophenotyping Identifies Shifts in the Circulating T-Cell Compartment Following Reperfusion in Patients with Acute Myocardial Infarction , 2012, PloS one.

[19]  C. Katlama,et al.  Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment , 2012, AIDS.

[20]  X. Yang,et al.  Mice Lacking NKT Cells but with a Complete Complement of CD8+ T-Cells Are Not Protected against the Metabolic Abnormalities of Diet-Induced Obesity , 2011, PloS one.

[21]  Michael N. Alonso,et al.  B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies , 2011, Nature Medicine.

[22]  J. Capeau,et al.  Glyceroneogenesis is inhibited through HIV protease inhibitor-induced inflammation in human subcutaneous but not visceral adipose tissue , 2011, Journal of Lipid Research.

[23]  Ò. Miró,et al.  Mitochondrial damage in adipose tissue of untreated HIV-infected patients , 2011, AIDS.

[24]  P. Mallon,et al.  Impact of mitochondrial toxicity of HIV-1 antiretroviral drugs on lipodystrophy and metabolic dysregulation. , 2010, Current pharmaceutical design.

[25]  F. Greenway,et al.  Obesity Increases the Production of Proinflammatory Mediators from Adipose Tissue T Cells and Compromises TCR Repertoire Diversity: Implications for Systemic Inflammation and Insulin Resistance , 2010, The Journal of Immunology.

[26]  HiroyukiTsutsui,et al.  Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice , 2010 .

[27]  D. Focosi,et al.  CD57+ T lymphocytes and functional immune deficiency , 2010, Journal of leukocyte biology.

[28]  Abigail Wacher,et al.  Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. , 2009, Blood.

[29]  V. Bourlier,et al.  Interplay Between Human Adipocytes and T Lymphocytes in Obesity: CCL20 as an Adipochemokine and T Lymphocytes as Lipogenic Modulators , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[30]  T. Kadowaki,et al.  CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity , 2009, Nature Medicine.

[31]  Christophe Benoist,et al.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters , 2009, Nature Medicine.

[32]  C. Vigouroux,et al.  Antiretroviral-Related Adipocyte Dysfunction and Lipodystrophy in HIV-Infected Patients: Alteration of the PPARγ-Dependent Pathways , 2008, PPAR research.

[33]  P. Libby,et al.  Interferon- (cid:1) , a Th1 Cytokine, Regulates Fat Inflammation A Role for Adaptive Immunity in Obesity , 2022 .

[34]  V. Hombach,et al.  T-lymphocyte Infiltration in Visceral Adipose Tissue: A Primary Event in Adipose Tissue Inflammation and the Development of Obesity-Mediated Insulin Resistance , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[35]  S. Weisberg,et al.  Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration , 2008, International Journal of Obesity.

[36]  Nina Friis-Møller,et al.  Incidence and Risk Factors for New-Onset Diabetes in HIV-Infected Patients , 2008, Diabetes Care.

[37]  C. Vigouroux,et al.  Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues , 2008, Antiviral therapy.

[38]  B. Palmer,et al.  CD57 expression correlates with alveolitis severity in subjects with beryllium-induced disease. , 2007, The Journal of allergy and clinical immunology.

[39]  B. Cousin,et al.  PPARs and Adipose Cell Plasticity , 2007, PPAR research.

[40]  Laxman Yetukuri,et al.  PPAR gamma 2 Prevents Lipotoxicity by Controlling Adipose Tissue Expandability and Peripheral Lipid Metabolism , 2007, PLoS genetics.

[41]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[42]  S. O’Rahilly,et al.  PPAR gamma and human metabolic disease. , 2006, The Journal of clinical investigation.

[43]  Denis Puthier,et al.  High Cytotoxic and Specific Migratory Potencies of Senescent CD8+CD57+ Cells in HIV-Infected and Uninfected Individuals1 , 2006, The Journal of Immunology.

[44]  S. O’Rahilly,et al.  PPARγ and human metabolic disease , 2006 .

[45]  B. Gazzard,et al.  Assessment of Adipokine Expression and Mitochondrial Toxicity in HIV Patients With Lipoatrophy on Stavudine- and Zidovudine-Containing Regimens , 2005, Journal of acquired immune deficiency syndromes.

[46]  B. Palmer,et al.  Functional and Phenotypic Characterization of CD57+CD4+ T Cells and Their Association with HIV-1-Induced T Cell Dysfunction1 , 2005, The Journal of Immunology.

[47]  Stephen R Cole,et al.  Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. , 2005, Archives of internal medicine.

[48]  A. Krensky,et al.  Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator 1 , 2005, The Journal of Immunology.

[49]  H. Côté,et al.  Possible Ways Nucleoside Analogues Can Affect Mitochondrial Dna Content and Gene Expression during HIV Therapy , 2005, Antiviral therapy.

[50]  R. Law,et al.  PPARγ-mediated insulin sensitization: the importance of fat versus muscle , 2005 .

[51]  L. Galluzzi,et al.  Changes in Mitochondrial Rna Production in Cells Treated with Nucleoside Analogues , 2005, Antiviral therapy.

[52]  J. Capeau,et al.  The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro , 2004, AIDS.

[53]  Tao Dong,et al.  Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection , 2004, PLoS biology.

[54]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[55]  B. Day,et al.  Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective , 2003, Nature Reviews Drug Discovery.

[56]  Nitin J. Karandikar,et al.  Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. , 2003, Blood.

[57]  A. Rudich,et al.  Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors , 2003, AIDS.

[58]  R. Mooney,et al.  Interleukin-6 induces cellular insulin resistance in hepatocytes. , 2002, Diabetes.

[59]  Y. Iwamoto,et al.  Involvement of CD4+,CD57+ T cells in the disease activity of rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[60]  P. Reiss,et al.  Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy , 1999, The Lancet.

[61]  J. Lisziewicz,et al.  Expansion of CD57 and CD62L-CD45RA+ CD8 T lymphocytes correlates with reduced viral plasma RNA after primary HIV infection. , 1999, AIDS.

[62]  A. Krensky,et al.  Processing, subcellular localization, and function of 519 (granulysin), a human late T cell activation molecule with homology to small, lytic, granule proteins. , 1997, Journal of immunology.

[63]  B. Spiegelman,et al.  IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance , 1996, Science.

[64]  T. Schall,et al.  The isolation and sequence of a novel gene from a human functional T cell line , 1987, The Journal of experimental medicine.

[65]  M. Ruth.  Normalization of obesity-associated insulin resistance through immunotherapy , 2010 .

[66]  A. Saltiel,et al.  Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. , 2007, American journal of physiology. Endocrinology and metabolism.

[67]  R. Law,et al.  PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. , 2005, American journal of physiology. Endocrinology and metabolism.

[68]  A. Rudich,et al.  Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. , 2005, Acta physiologica Scandinavica.