T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection

Abstract

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…Our results also demonstrate that PD-1 levels are increased among CD27 + CD8 + T cells in HIV-TB patients, providing new evidence pointing to an exhausted phenotype restricted to those cells that home to lymph nodes. These results are in line with the association of PD1 expression to a T-bet low /Eomes hi transitional memory phenotype in CD8 + T cells from HIV + patients observed by Buggert et al [31]. Strikingly, our observation of a positive correlation between PD-1 expression on CD27 + CD8 + T cells (a population that includes T N , T CM , and transitional memory cells) and % CD45RA dim cells in T TE points to an arrest of exhausted cells on less functional phenotypes as observed in HIV + patients [31].…”

“…These results are in line with the association of PD1 expression to a T-bet low /Eomes hi transitional memory phenotype in CD8 + T cells from HIV + patients observed by Buggert et al [31]. Strikingly, our observation of a positive correlation between PD-1 expression on CD27 + CD8 + T cells (a population that includes T N , T CM , and transitional memory cells) and % CD45RA dim cells in T TE points to an arrest of exhausted cells on less functional phenotypes as observed in HIV + patients [31]. Several authors have explored the dynamics of Mtb-specific CD4 + T cells but just a few studies have been focused on Mtbspecific CD8 + T cells.…”

“…These results suggest an association between increased proportions of not fully differentiated CD8 + T cells (in terms of CD45RA expression) and elevated percentages of exhausted CD27 + CD8 + T cells in HIV-TB patients. A higher expression of PD-1 in the CD27 + population and a positive correlation between PD-1 expression on CD27 + CD8 + T cells and CD45RA dim cells in T TE could imply an arrest of exhausted cells on a less differentiated and poor functional phenotype as observed in HIV + patients [31]. To sum up, these results suggest an impaired differentiation occurring concomitantly with an increased exhaustion of CD8 + T cells, both associated to HIV-TB coinfection.…”

Infection History Determines the Differentiation State of Human CD8 + T Cells

“…We and others have recently shown that T-bet and Eomes expression varies in human CD8 ϩ T-cell subsets and virus-specific populations (6,(25)(26)(27)(28). Furthermore, their expression levels were also shown to distinctly correspond to the expression of IL-7R␣, granzymes, and various coinhibitory receptors expressed by exhausted CD8 ϩ T cells (26,27,29). Here, we show that the T-bet and Eomes expression state of an individual CD8 ϩ T-cell corresponds to specific functional traits in a manner that is irrespective of the differentiation status defined by the CD45RA/CCR7/CD28/CD27 subdivision.…”

Differential Impact of In Vivo CD8 + T Lymphocyte Depletion in Controller versus Progressor Simian Immunodeficiency Virus-Infected Macaques

“…Statistical analyses were performed using Mann-Whitney U tests. mans (32,33). The high predepletion levels of T-bet expression in SIV-infected progressors may reflect the high levels of activation and antigenic load which resulted from the poor control of virus occurring in progressors.…”