Phenotype, Function, and Gene Expression Profiles of Programmed Death-1hi CD8 T Cells in Healthy Human Adults

Abstract

T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and PD-1hi cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, hepatitis C virus, and hepatitis B virus. However, it is not known if PD-1hi cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function, and gene expression profiles of PD-1hi versus PD-1lo CD8 T cells in the peripheral blood of healthy human adults as follows: 1) the percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans, and PD-1 was expressed by the memory CD8 T cells; 2) PD-1hi CD8 T cells in healthy humans did not significantly correlate with the PD-1hi exhausted gene signature of HIV-specific human CD8 T cells or chronic lymphocytic choriomeningitis virus-specific CD8 T cells from mice; 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults; 4) PD-1 was expressed by the effector memory compared with terminally differentiated effector CD8 T cells; and 5) finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. In conclusion, our study shows that most PD-1hi CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells.

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

“…17 It should be noted that our gene expression profiling was performed after a period of expansion of isolated TIL with IL-2 in order to generate enough cells for analysis. This may have reversed an exhausted state and its associated gene expression profile in the BTLA C cells that may have been detectable if the TIL were analyzed directly ex vivo.…”

“…C PD-1 ¡ CD45RA C T EMRA cells in lymphocytes from normal donors, 17,18 and senescent human CD8 C CD28 ¡ T cells. 19,20 We confirmed the preferential protein expression of some KIR receptors in the CD8 C BTLA ¡ subset by flow cytometry (Fig.…”

Influenza infection results in local expansion of memory CD8+ T cells with antigen non-specific phenotype and function

“…S2e,f). While PD-1 is widely known for its function as an inhibitory mediator, it is also known to function as an acute activation marker present on effector/ effector memory cells [31,32]. Given that our previous studies involving immunotherapy focused primarily on secondary lymphoid organs, we reasoned that tissue-resident memory cells, such as those found in the lung, are generally of the effector memory phenotype and may up-regulate representative of at least five independent experiments.…”

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…However, recent studies have revealed that PD-1 is also transiently expressed on the surface of effector T cells during earlier stages of activation (2,3). PD-1 mediates its inhibitory effect by clustering with the T-cell receptor (TCR) in the immunologic synapse and, after contacting either of its two known ligands (PD-L1 or PD-L2), recruiting SHP-2 phosphatase to its intracellular immunoreceptor tyrosine-based switch motif (ITSM; ref.…”