High Eomesodermin Expression among CD57 ⁺ CD8 ⁺ T Cells Identifies a CD8 ⁺ T Cell Subset Associated with Viral Control during Chronic Human Immunodeficiency Virus Infection

Abstract

During HIV infection, increased CD57 expression among CD8؉ T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8؉ T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8 ؉ T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8 ؉ T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8 ؉ T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8 primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES hi CD57؉ cells among HIV-specific and nonspecific CD8 ؉ T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES hi CD57 ؉ phenotypic profile was associated with viral control. IMPORTANCEThis study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES int CD57 ؉ CD8 ؉ T cells and less differentiated EOMES hi CD57 ؉ CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES hi CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.

NK Cell Functional Impairment after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Reduced Levels of T-bet and Eomesodermin

“…We also found that, similarly to what we recently reported for CD8 T cells (24), T-bet upregulation during NK terminal differentiation occurred concomitantly with progressive Eomes downregulation. These results suggest that T-bet and Eomes in cytotoxic lymphocytes are coexpressed in differential gradients that seem to regulate cytotoxic cell effector functions.…”

Continuous Effector CD8 + T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population

“…Eomes, and the related transcription factor T-bet play partially redundant roles in CD8+ T cells, although Eomes also plays unique roles in the maintenance of memory and exhausted T cells (Banerjee et al, 2010; Intlekofer et al, 2005; Paley et al, 2012). Interestingly, high Eomes expression is also associated with a proliferative subset of CD8+ T cells found in some HIV-infected individuals, and correlates with effective viral control (Simonetta et al, 2014). Moreover, Eomes is highly expressed in intermediate neural progenitor cells, where it is required for the maintenance of the intermediate population and ongoing neurogenesis (Hodge et al, 2012).…”

Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens

“…Of note, the expansion of CD57 + CD8 + T-cells is a hallmark of latent CMV infection (35). The CD57 + CD8 + T-cell subset is functionally heterogeneous, and includes highly cytotoxic T TE cells that express intermediate levels of EOMES, as well as non-cytotoxic EOMES hi T TE cells with high proliferative capacity (36). These above-referenced studies highlight the existence of functional heterogeneity among the CD8 + T-cell memory subsets.…”

“…Furthermore, targeting peripheral blood pro-inflammatory CD28 − T-cells and NK-like CD8 + T-cells by inhibiting CD137 expression may possibly be of relevance to the treatment of bronchiolitis obliterans syndrome (50). In this regard, the percentage of CD57 + CD8 + T-cells is the strongest immunologic predictor of future cutaneous squamous cell carcinoma and was correlated with increasing CD8 + T-cell differentiation (36). As mentioned above, a high percentage of CD57 + CD8 + T cells are NK-like.…”