Restoring function in exhausted CD8 T cells during chronic viral infection

Abstract

Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.

The (gradual) rise of memory inflation

“…This molecular pattern suggests homing to non‐lymphoid tissues and indeed the second feature is accumulation not only in blood and spleen where it was first noted but in many such tissues such as lung and liver, as opposed to lymph nodes 1, 3, 13. The third feature observed was maintained effector functions such as cytokine release—in contrast to exhausted CD8 + T cells 8. There are certainly some differences in the level of cytokine production comparing inflationary populations and classical non‐inflationary memory cells in the same model, but over time there does not appear to be clear attrition of such functionality (and the lack of transcriptional and phenotypic markers of exhaustion is consistent with this) 3, 4, 16, 17.…”

“…Features of immune exhaustion include surface marker expression (eg, PD1), in vitro functionality (eg, cytokine release), metabolic dysfunction, and disruption of transcriptional networks 8, 9, 45, 46…”

“…Again, the term is a clear and useful description of the phenomenon seen, although a spectrum of exhaustion phenotypes can be seen even within the same animal, which varies over time and between specificities. Following work by other groups, the phenomenon was redefined using a more graded system based on analysis of specific functions but it was not until the identification of specific markers linked to the gene expression profile of exhausted T cells discovered by the group of Rafi Ahmed over a decade later, that the phenomenon took on a more concrete mechanistic explanation 8. Even so, expression of single molecular markers such as PD‐1 is insufficient to really provide the pinpoint definition that would be ideal, and definitions based on gene expression or epigenetic regulation are somewhat complex 9.…”

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…PD‐1 is an exhausted T‐cell marker (Barber et al ., 2006). Long‐term eRapa significantly reduced PD‐1 + CD4 + and PD‐1 + CD8 + T‐cell prevalence in aged mice (Fig.…”

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…For instance, in chronic lymphocytic choriomeningitis virus (LCMV)‐infected mice, PD‐1 is highly expressed on the surface of T cells compared to functional memory T cells, and these PD‐1 + CD8 + T cells fail to proliferate when stimulated, display defects in effector functions, and are called exhausted T cells (Barber et al ., 2006). Exhausted T cells have also been identified in different viral infections, such as HIV and hepatitis A and B virus (Sharpe et al ., 2007; Keir et al ., 2008).…”