HIV-1 Tat affects the programming and functionality of human CD8⁺ T cells by modulating the expression of T-box transcription factors.
OBJECTIVE
HIV infection is characterized by several immune dysfunctions of both CD8⁺ and CD4⁺ T cells as hyperactivation, impairment of functionality and expansion of memory T cells. CD8⁺ T-cell dysfunctions have been associated with increased expression of T-bet, Eomesdermin and pro-inflammatory cytokines, and with down-regulation of CD127. The HIV-1 trans-activator of transcription (Tat) protein, which is released by infected cells and detected in tissues of HIV-positive individuals, is known to contribute to the dysregulation of CD4⁺ T cells; however, its effects on CD8⁺ T cells have not been investigated. Thus, in this study, we sought to address whether Tat may affect CD8⁺ T-cell functionality and programming.


METHODS
CD8⁺ T cells were activated by T-cell receptor engagement in the presence or absence of Tat. Cytokine production, killing capacity, surface phenotype and expression of transcription factors important for T-cell programming were evaluated.


RESULTS
Tat favors the secretion of interleukin-2, interferon-γ and granzyme B in CD8⁺ T cells. Behind this functional modulation we observed that Tat increases the expression of T-bet, Eomesdermin, Blimp-1, Bcl-6 and Bcl-2 in activated but not in unstimulated CD8⁺ T lymphocytes. This effect is associated with the down-regulation of CD127 and the up-regulation of CD27.


CONCLUSIONS
Tat deeply alters the programming and functionality of CD8⁺ T lymphocytes.
aDepartment of Life Sciences and Biotechnology, University of Ferrara, Ferrara bLaboratory of Translational Immunology, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan cNational AIDS Center, Istituto Superiore di Sanità, Rome dDepartment of Molecular Medicine, University of Padova, Padova, Italy. *Dr Fabio Sforza and Dr Francesco Nicoli contributed equally to the writing of this article.
Fabio
F
Sforza
Francesco
F
Nicoli
Eleonora
E
Gallerani
Valentina
V
Finessi
Eva
E
Reali
Aurelio
A
Cafaro
Antonella
A
Caputo
Barbara
B
Ensoli
Riccardo
R
Gavioli
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D058501:Enzyme-Linked Immunospot Assay; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus