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During chronic viral infections, such as with hepatitis C virus (HCV), antigen-specific T cells are persistently exposed to viral antigens, resulting in increased T cell turnover and the depletion of long-lived T cell populations. This can lead to the eventual 'collapse' of the adaptive immune response. This study identifies separate populations of progenitor and terminally differentiated virus-specific CD8+ T cells that are present in chronic infection and must be balanced to maintain a durable response. These populations could be distinguished by differential expression of the T-box transcription factors T-bet and eomesodermin (EOMES).

it is the progenitor–progeny relationship between T-bethi and EOMEShi CD8+ T cells that is the crucial factor in maintaining a virus-specific response

In mice chronically infected with lymphocytic choriomeningitis virus (LCMV), T-bet and EOMES were reciprocally expressed by LCMV-specific CD8+ T cells. The EOMEShi T cells had higher levels of expression of inhibitory receptors such as PD1 and produced lower levels of pro-inflammatory cytokines than T-bethi T cells, but had greater cytotoxicity. The EOMEShi T cells outnumbered T-bethi T cells by a factor of ∼20 overall. Furthermore, the EOMEShi T cells showed evidence of recent extensive proliferation but were not currently dividing. Genetic deletion of Tbx21 (which encodes T-bet) resulted in increased EOMES and PD1 expression by CD8+ T cells and increased proliferation, whereas deficiency of EOMES led to increased T-bet expression and cytokine production, decreased PD1 expression and decreased proliferation. Thus, T-bet and EOMES mark distinct but related populations of CD8+ T cells during chronic infection, with different regenerative and antiviral capacities.

The authors then used adoptive-transfer experiments to examine the lineage relationship between these two populations. LCMV-specific PD1hiEOMEShi CD8+ T cells divided only modestly and retained high expression levels of PD1 after transfer to LCMV-infected hosts, whereas transferred PD1intT-bethi T cells underwent extensive proliferation in vivo, which was associated with their conversion to PD1hi cells. The conditional deletion of Tbx21 from LCMV-specific CD8+ T cells before transfer to infected hosts increased conversion to PD1hi cells, suggesting that T-bet has a crucial role in maintaining the PD1intT-bethi progenitor population. By contrast, conditional deletion of Eomes decreased the size of the PD1hi cell population, which suggests that EOMES is crucial for the generation of PD1hi progeny.

In the absence of either T-bet or EOMES, virus-specific CD8+ T cells were unable to sustain an effective antiviral response. However, in mixed chimaeras, the combination of Eomes−/− T-bethi and Tbx21−/− EOMEShi T cells did not improve viral control over either population alone. It therefore seems that it is the progenitor–progeny relationship between T-bethi and EOMEShi CD8+ T cells that is the crucial factor in maintaining a virus-specific response, rather than some form of cooperation between distinct functions of the two populations.

Persistent antigen exposure was required for the proliferation of T-bethi T cells and their conversion to EOMEShi T cells, but EOMES expression was retained after antigen removal, which indicates that the EOMEShi progeny are terminally differentiated. So the authors suggest that if chronic antigen exposure induces T-bethi precursors to continually proliferate and give rise to EOMEShi terminally differentiated progeny, then chronic infection could eventually deplete the T-bethi population. Indeed, in patients infected with HCV, there was a marked accumulation of EOMEShi HCV-specific CD8+ T cells and a depletion of T-bethi cells in the liver during chronic infection (as compared with cell numbers following the resolution of infection).

In summary, the findings suggest that a crucial balance between T-bethi CD8+ T cell precursors with regenerative capacity and EOMEShi progeny with cytotoxic activity must be maintained during chronic infection to support the antiviral T cell response.