T cell ‘exhaustion’ may represent an adaptive state of differentiation, rather than a dysfunctional state for over-stimulated T cells during chronic viral infection, according to a report published in Nature Immunology. Further understanding of the mechanisms controlling T cell exhaustion could provide important insight into therapies for persistent viral infections, such as HIV and hepatitis C virus, or cancer.

In chronic viral infections, repeated stimulation by the virus and persistent inflammation triggers T cell ‘exhaustion’, a process that involves the progressive loss of function and ultimately death of the virus-specific T cells. This is in contrast to acute viral infection, which generates functional effector T cells and memory T cells that can coordinate a secondary immune response in case of re-encounter with the same virus. Dietmar Zehn and colleagues now show that ‘exhausted’ T cells isolated from mice infected with a strain of lymphochoriomeningitis virus (LCMV) that causes chronic infection were able to proliferate and mediate efficient responses when transferred to recipient mice infected with a LCMV strain that causes acute infection. These results suggest that T cell exhaustion could be a stable and controlled stage of T cell differentiation imposed by the specific environment of chronic infections, but not a non-functional one.