T-cell exhaustion due to persistent antigen: quantity not quality?

Abstract

T-cell exhaustion is characterized by failure to respond to a persistent antigen and is a hallmark of chronic infections and cancer. Here, we discuss several recent reports on T-cell exhaustion, including one in this issue of the European Journal of Immunology where Richter et al. [Eur. J. Immunol. 42:2290-2304] examine the importance of the amount of persistent antigen versus the cell type presenting it to induce CD8(+) T-cell exhaustion, and the consequences for host survival during chronic viral infection.

Figure 1. Antigen dose dictates T cell function during chronic infection

This cartoon depicts the major role of antigen in driving CD8⁺ T cell function and exhaustion. During priming antigen is presented to naïve CD8⁺ T cells by dendritic cells leading to their activation and proliferation. At later stages of chronic infection exhaustion occurs as a result of excessive antigen presentation provided by both directly infected cells or antigen bearing professional APCs (DCs, B cells etc). This is characterized by reduced expression of functional molecules such as IL-2, TNFα and IFN-γ and increased expression of inhibitory molecules such as PD-1. Reduction of antigen burden, in the presence of ongoing infection, can result in CD8⁺ T cell mediated immunopathology, where function is restored to the CD8⁺ T cells without rapid resolution of infection. Clearance can be seen when MHC:TCR interactions reduce to a level that does not result in T cell exhaustion and pathogen load can be successfully resolved by the anti-viral CD8 T cell response.