Regulation of CD28 costimulation in human CD8+ T cells.
Optimal stimulation and prevention of anergy in T cells requires signaling through the CD28 molecule. During HIV disease progression, CD28 expression is lost, particularly on CD8+ T cells. Because alterations in cytokine production patterns occur during HIV infection, we determined whether CD8+ T cell phenotype or function was affected by cytokine environment. Treatment of CD8+ T cells with IL-4 decreased levels of both CD28 surface expression and message and increased CD8 expression. Furthermore, CD8+ T cells that had down-regulated CD28 had reduced proliferative capacity. The inhibitory effects of CD28 reduction could be compensated either by increased anti-CD3 or by exogenous IL-2, suggesting that the strength of T cell signaling necessary for the production of IL-2 and subsequent proliferation is negatively regulated by IL-4. CD8+ subpopulations with differential CD28 expression produced different patterns of cytokines, particularly IL-2 and IFN-gamma. Furthermore, CD8+ T cells that had reduced CD28 levels but made their own IL-2 were able to proliferate in response to TCR stimulation. These results suggest that loss of CD28 expression and CD8 T cell function can be regulated by the cytokine environment, which may be altered during HIV disease progression. Whether the dysfunction of CD8+ T cells in HIV infection occurs by such a mechanism is the subject of future investigation.
Lloyd
T E
TE
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Yang
L
L
Tang
D N
DN
Bennett
T
T
Schober
W
W
Lewis
D E
DE
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D016827:CD8 Antigens / Q000096:biosynthesis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D012333:RNA, Messenger / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D016827:CD8 Antigens; D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger; D015847:Interleukin-4