In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.

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Molecular and cellular insights into T cell exhaustion

HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T-cells

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(08)61591-3.pdf

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.

Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.

Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment

A recombinant virus assay was used to characterize in detail neutralizing antibody responses directed at circulating autologous HIV in plasma. Examining serial plasma specimens in a matrix format, most patients with primary HIV infection rapidly generated significant neutralizing antibody responses to early (0–39 months) autologous viruses, whereas responses to laboratory and heterologous primary strains were often lower and delayed. Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been underappreciated based on earlier, less comprehensive characterizations. These data argue that neutralizing antibody responses account for the extensive variation in the envelope gene that is observed in the early months after primary HIV infection.

https://www.pnas.org/content/pnas/100/7/4144.full.pdf

Rapid evolution of the neutralizing antibody response to HIV type 1 infection

To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.

/pdf/dramatic-rise-in-plasma-viremia-after-cd8-t-cell-depletion-5a84bv1t2f.pdf

Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques

INTRODUCTION
Case studies and retrospective chart reviews of health system data have demonstrated an increased risk of nephrotoxicity in patients receiving immune checkpoint inhibitors compared to clinical trials. This study investigated the frequency, causes, and risk factors for acute kidney injury in a real-world, rural setting.


METHODS
This was a retrospective cohort study of patients who received at least one dose of a checkpoint inhibitor at a rural health system from May 2013 to February 2020 and who received at least one dose of a checkpoint inhibitor. Electronic and manual chart review helped to determine the incidence of, risk factors for, and renal outcomes and management strategies of checkpoint inhibitor-related acute kidney injury. Multivariable Fine and Gray subdistribution hazard models were used to assess the impact of patient characteristics on the incidence of sustained acute kidney injury and checkpoint inhibitor-induced acute kidney injury.


RESULTS
After exclusion criteria, 906 patients who received at least one dose of a checkpoint inhibitor at Marshfield Clinic Health System during the study period were included. The incidence of acute kidney injury of any duration and due to any cause was 36.1%, while sustained acute kidney injury occurred in 28.7% of patients. Checkpoint inhibitor-related acute kidney injury was thought to have occurred in 2.7% of patients. Baseline estimated glomerular filtration rate < 60 was the sole predictor of checkpoint inhibitors-related acute kidney injury. Most patients with suspected checkpoint inhibitor-related acute kidney injury were managed with corticosteroids, and 62.5% experienced complete renal recovery.


CONCLUSIONS
Ours is the first retrospective cohort study to test whether baseline Eastern Cooperative Oncology Group score and checkpoint inhibitor place in therapy were associated with checkpoint inhibitor-related acute kidney injury, and neither of these data points were found to be predictive. Even after expanding the parameters and methodologies of our study as compared to other retrospective cohort studies, we found only three baseline characteristics to be predictive of sustained acute kidney injury: Baseline eGFR, loop diuretic, and spironolactone use. For checkpoint inhibitor-related baseline, eGFR alone was predictive.

Craig E. Irwin

Papers

Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques

Cohort study on immune checkpoint inhibitor-associated acute kidney injury: Incidence, risk factors, and management strategies.