Bystander hyperactivation of preimmune CD8 ⁺ T cells in chronic HCV patients

Abstract

Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8 ⁺ T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8 ⁺ T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8 ⁺ T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.

DOI: http://dx.doi.org/10.7554/eLife.07916.001

eLife digest

Long-lasting or “chronic” infections massively perturb the immune system as a way to favor their own growth. In particular, they can stop T cells – a subtype of immune cells that help to destroy viruses – from working well. For example, HIV and hepatitis C viruses can overwork T cells and cause them to die. This can make individuals vulnerable to other infections.

In healthy people, T cells that have participated in the fight against particular infections continue to live to provide a memory of those past infections. Groups of “naïve” T cells that have not yet encountered an infected cell also patrol the body, ready to respond to infections by a new virus. There are relatively few virus-specific naïve T cells in the body, so until recently it has been hard to study them. As a result, researchers know little about how these cells are affected by long-lasting infections, and whether chronic infection affects our capacity to fight unrelated infections.

Alanio et al. have now used a highly sensitive technique to compare naïve T cells found in the blood of three groups of people: those with chronic hepatitis C infections, those who have been cured of a chronic hepatitis C infection, and healthy people. This revealed that the naïve T cells are negatively affected by chronic hepatitis C infections, and become hypersensitive: they get easily overexcited, which can lead to their death. This compromises the immune defenses at the moment they are most needed.

Closer inspection showed that the naïve T cells of patients with hepatitis C are hypersensitive because they have less of a protein called CD5 on their surface. This protein acts as a natural brake for the T cells, and thus having less results in the T cells mounting stronger immune responses. Although this might be beneficial when fighting certain infections, this may also account for conditions where T cells attack healthy tissues.

Finally, Alanio et al. found evidence that people who have been cured of a chronic hepatitis C infection recover a healthy set of naïve T cells within two years. Treating patients as soon as an infection is diagnosed therefore has several benefits: as well as clearing the virus, this will reset the immune system balance and reduce the damage that hyperactive immune cells cause to the body.

The results also have implications for vaccinations, which work by pushing naïve T cells to arm themselves against a particular virus. The discovery that naïve T cells are hypersensitive in patients with hepatitis C suggests that we may need a distinct strategy for efficiently vaccinating these patients. It is indeed possible that standard vaccines – tested in groups of healthy people – may result in unexpected and unwanted immune responses in individuals with hepatitis C.

These open questions will be addressed in further studies. It will also be of interest to know if other chronic viruses have the same ability to alter the activity of naïve T cells.

DOI: http://dx.doi.org/10.7554/eLife.07916.002