Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex.
Although human immunodeficiency virus (HIV)-infected subjects without acquired immunodeficiency syndrome have a high frequency of HIV-specific CD8 T lymphocytes, freshly isolated lymphocytes frequently lack detectable HIV-specific cytotoxicity. However, this effector function becomes readily apparent after overnight culture. To investigate reasons for T-cell dysfunction, we analyzed T-cell expression of the cytolytic protease granzyme A and CD3 zeta, the signaling component of the T-cell receptor complex. An increased proportion of CD4 and CD8 T cells from HIV-infected donors contain granzyme A, consistent with the known increased frequency of activated T cells. In 28 HIV-infected donors with mild to advanced immunodeficiency, a substantial fraction of circulating T cells downmodulated CD3 zeta (fraction of T cells expressing CD3 zeta, 0.74 +/- 0.16 v 1.01 +/- 0.07 in healthy donors; P < .0000005). CD3 zeta expression is downregulated more severely in CD8 than CD4 T cells, decreases early in infection, and correlates with declining CD4 counts and disease stage. CD3 zeta expression increases over 6 to 16 hours of culture in an interleukin-2-dependent manner, coincident with restoration of viral-specific cytotoxicity. Impaired T-cell receptor signaling may help explain why HIV-specific cytotoxic T lymphocytes fail to control HIV replication.
Trimble
L A
LA
Center for Blood Research, Harvard Medical School, Boston, MA, USA.
Lieberman
J
J
D017252:CD3 Complex / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015536:Down-Regulation; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
D017252:CD3 Complex; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell