The role, relevance and management of immune exhaustion in bovine infectious diseases

Abstract

Immune exhaustion is a state of immune cell dysfunction that occurs most commonly following chronic exposure to an antigen which persists after the immune response fails to remove it. Exhaustion has been studied most thoroughly with several cancers, but has also been observed in several chronic infectious diseases. The topic has mainly been studied with CD8⁺ T cells, but it can also occur with CD4⁺ T cells and other immune cell types too. Exhaustion is characterized by a hierarchical loss of effector cell functions, up-regulation of immuno-inhibitory receptors, disruption of metabolic activities, and altered chromatin landscapes. Exhaustion has received minimal attention so far in diseases of veterinary significance and this review's purpose is to describe examples where immune exhaustion is occurring in several bovine disease situations. We also describe methodology to evaluate immune exhaustion as well as the prospects of controlling exhaustion and achieving a more suitable outcome of therapy in some chronic disease scenarios.

Keywords: B cells; Bovine; Cytokines; Exhaustion; Immune; Immuno-inhibitory receptors; T cells-CD4 and CD8.

Fig. 1

A Upon activation naive cells become activated effector T cell (T helperTh1/T cytotoxic Tc1). Activated effector T cells up-regulates TIM-3 (an immuno-inhibitory receptor) which upon binding to its ligand galectin 9 (expressed on innate cells and other immune cells) or available as soluble form, result in apoptosis of TIM-3 bearing effector T cells. This results in dampening of the immune response which might otherwise result in immuno-pathology due to excessive cytokine production by the immune effector cells. Remaining cells down regulates TIM-3 after peak of an immune response. Thus TIM-3-Galectin 9 is an immunoregulatory pathway. Fig. 1B High PD-L1 expression is expressed in the thymus and on dendritic cells, where the PD-L1/PD-1 interaction prevents the proliferation and differentiation of naïve T cells. PD-1-PD-L1 pathway is also involved in immune exhaustion. Persistent up-regulation of PD-1 is expressed on tumour-infiltrating lymphocytes, where PD-L1 expression is exploited by malignant cells to avoid immune destruction (an immune evasion strategy by tumor cells).

Fig. 2

Co-expression of TIM-3 and PD-1 Correlates with a severe exhaustion of immune cells during chronic infections and tumors. TIM-3⁺PD-1⁺ Exhausted T Cell Produces Inhibitory Cytokines.