title: CD4⁺CD28null T lymphocytes resemble CD8⁺CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients.
abstract: HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain.
authors.forename: Ainara
authors.initials: A
authors.lastname: Echeverría
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Moro-García
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Asensi
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Cartón
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
authors.affiliation: *Immunology Department and Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; and Fundación Renal "Iñigo Alvarez de Toledo," Madrid, Spain ralonsoarias@hotmail.es.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Alonso-Arias
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D003710:Demography; D005260:Female; D053804:Granzymes / Q000378:metabolism; D015488:HIV Antigens / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult; D000098546:Interleukin-21; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D053804:Granzymes; D015488:HIV Antigens; D007371:Interferon-gamma; D019409:Interleukin-15; D007378:Interleukins; D037181:Lectins, C-Type; D054353:Perforin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D025521:Tumor Suppressor Proteins; D000098546:Interleukin-21; D000099192:CD69 Antigens; C494086:STAT3 protein, human; C494092:STAT5A protein, human
keywords: T lymphocyte differentiation; cytotoxicity; immunosenescence