Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects

Abstract

SUMMARY The CD28 receptor on CD4+ and CD8+ T cells interacts with B7 molecules on antigen‐presenting cells (APC) to generate essential costimulatory signals. The cytolytic potential of CD8+ T cells could be linked to CD28 expression. Since HIV induces dysfunction of both CD4+ and CD8+ T cells, we evaluated CD28 expression and function in both subsets during HIV infection. CD28 expression on CD8+ T cells from HIV+ subjects was strongly reduced in a disease stage‐related fashion. CD28‐CD8+ T cells preferentially expressed CD57 and CD11b, but lacked CD26 and IL‐2Rα. The CD8+ T cells from the patients showed a significantly reduced proliferative response to co‐stimulation with cell‐bound anti‐CD3 and B7. Nevertheless, when stimulated with plate‐fixed anti‐CD3, CD8+ T cells from HIV‐infected subjects proliferated normally, and normal levels of IL‐2Rα nod transferrin‐receptor could be induced on CD28‐CD8+ T cells from the patients. In addition, stimulation with plate‐fixed anti‐CD3 induced proliferative responses in highly purified CD28‐CD8+ T cells from both HIV‐ and HIV+ persons. Furthermore, the increased cytotoxic activity of peripheral blood mononuclear cells (PBMC) from HIV+ subjects, measured in an anti‐CD3 redirected assay, was predominantly exerted by CD28‐CD57+ T cells. CD4+ T cells from the patients showed a slight but significant CD28 down‐regulation and were slightly hyporesponsive to B7 co‐stimulation. Decrease of CD28 on CD8+ T cells from HIV+ subjects is associated with an impaired response to co‐stimulation via B7. CD28‐CD8+ T cells from seropositives, however, are not completely inert, since they contain in vivo activated CTL and they can be additionally activated through a B7‐independent stimulation.

Impaired function of human T-lymphotropic virus type 1 (HTLV-1)–specific CD8+ T cells in HTLV-1–associated neurologic disease

“…Especially, increased expression of CD8 ϩ CD28 Ϫ T cells was associated with disease activity and CD8 ϩ T-cell dysfunction in HIV infection. 30,31 As expected, the percentages of CD8 ϩ cells that were negative for CD28 or CD27 were significantly increased in patients with HAM/TSP by comparison with HVCs or HCs, irrespective of PVL.…”

Significantly skewed memory CD8+ T cell subsets in HIV-1 infected infants during the first year of life

“…These phenotypes have been shown to be prevalent in HIV − infected adults with high viremia, where the senescent T cells have also shown reduced proliferative capacity [9; 45]. Similarly, adults [46; 47; 48; 49; 50] and children [14; 21] with high viral replication characteristically have CD8 + T cell downregulation of CD28, which leads to dysregulation of normal T cell function. Interestingly, we found that HIV-exposed but uninfected infants expressed significantly lower levels of CD57 than HIV-1 unexposed infants.…”

Dynamics of T cell memory in human cytomegalovirus infection

“…NonspeciWc stimulation using anti-CD3, anti-CD2, PHA or PMA + ionomycin has shown CD28¡ T cells have a lesser capacity for proliferation than CD28+ T cells [70,[103][104][105][106]. However, this has not been replicated in other studies using plate-bound anti-CD3 stimulation [107] or autologous PHA-stimulated blast cells as stimulators in HIVinfected subjects [108]. CD28¡ and CD28+ CD8+ T cells have also been shown to have a similar cloning eYciency, however, greater numbers of progeny were derived from CD28+ precursors [70].…”