27087

B3GAT1

beta-1,3-glucuronyltransferase 1;B3GAT1;beta-1,3-glucuronyltransferase 1

LEU7 antigen|UDP-GlcUA:glycoprotein beta-1,3-glucuronyltransferase|galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1|glcUAT-P|glucuronosyltransferase P

11q25

protein-coding

Virus-specific CD8(+) T-cell responses play a pivotal role in limiting viral replication. Alterations in these responses, such as decreased cytolytic function, inappropriate maturation, and limited proliferative ability could reduce their ability to control viral replication. Here, we report on the capacity of HIV-specific CD8(+) T cells to secrete cytokines and proliferate in response to HIV antigen stimulation. We find that a large proportion of HIV-specific CD8(+) T cells that produce cytokines in response to cognate antigen are unable to divide and die during a 48-hour in vitro culture. This lack of proliferative ability of HIV-specific CD8(+) T cells is defined by surface expression of CD57 but not by absence of CD28 or CCR7. This inability to proliferate in response to antigen cannot be overcome by exogenous interleukin-2 (IL-2) or IL-15. Furthermore, CD57 expression on CD8(+) T cells, CD4(+) T cells, and NK cells is a general marker of proliferative inability, a history of more cell divisions, and short telomeres. We suggest, therefore, that the increase in CD57(+) HIV-specific CD8(+) T cells results from chronic antigen stimulation that is a hallmark of HIV infection. Thus, our studies define a phenotype associated with replicative senescence in HIV-specific CD8(+) T cells, which may have broad implications to other conditions associated with chronic antigenic stimulation.

Killer cell lectin-like receptor G1 (KLRG1) is one of several inhibitory killer cell lectin-like receptors expressed by NK cells and T lymphocytes, mainly CD8(+) effector/memory cells that can secrete cytokines but have poor proliferative capacity. Using multiparameter flow cytometry, we studied KLRG1 expression on CD8(+) T cells specific for epitopes of CMV, EBV, influenza, and HIV. Over 92% of CD8(+) cells specific for CMV or EBV expressed KLRG1 during the latent stage of these chronic infections. CD8(+) T cell cells specific for HIV epitopes were mostly (72-89%) KLRG1(+), even though not quite at the level of predominance noted with CMV or EBV. Lower frequency of KLRG1 expression was observed among CD8(+) cells specific for influenza (40-73%), a resolved infection without a latent stage. We further observed that CD8(+) cells expressing CD57, a marker of replicative senescence, also expressed KLRG1; however, a population of CD57(-)KLRG1(+) cells was also identified. This population may represent a "memory" phenotype, because they also expressed CD27, CD28, CCR7, and CD127. In contrast, CD57(+)KLRG1(+) cells did not express CD27, CD28, and CCR7, and expressed CD127 at a much lower frequency, indicating that they represent effector cells that are truly terminally differentiated. The combination of KLRG1 and CD57 expression might thus aid in refining functional characterization of CD8(+) T cell subsets.