HHV-6 infection induces a high percentage of virus-specific suppressive Tregs compared to CMV

A French group studied immunological responses to HHV-6 and CMV in healthy adults ex vivo  and found that HHV-6 induces an excessive number of potently immunosuppressive T regulatory cells that block dendritic cell maturation and functions.

To compare immunological responses to HHV-6 and CMV in healthy adults, a team of investigators led by Delphine Sauce at INSERM studied the CD4+ and CD8+ T-cell responses from peripheral blood mononuclear cells (PBMCs) of blood donors and found that, compared to CMV, HHV-6 induces a high frequency of virus-specific regulatory T (Treg) cells and fewer late-differentiated effector T cells. This data corroborates previous reports, which have also found HHV-6A (Wang 2014) and HHV-6B (Wang 2006) capable of inducing CD4+ and CD8+ HHV-6-specific Tregs, which are immunosuppressive and block dendritic cell maturation and functions.

HHV-6 has been noted to have immunosuppressive qualities, which might contribute to the diseases the virus is associated with, and by lowering immune defenses, immunosuppression may also enable other pathogens to take hold in the body. Just how HHV-6 can dampen the immune system, as well as the extent of immunosuppression, has not yet been fully characterized.

As HHV-6-specific T cells are very sparse in ex vivo blood samples from healthy donors, it is difficult to detect and characterize them without performing in vitro expansion. The team was, however, able to do so using flow cytometry to analyze the frequency of CD4+ and CD8+ T cells secreting either IFN-gamma or TNF-alpha in response to CMV, HHV-6A, or HHV-6B lysate. Stimulation with the HHV-6 proteins U54 and U90 was also performed to detect and characterize antigen-specific T cells. Blood samples were obtained from 11 healthy donors who were seropositive for both viruses. Ex vivo HHV-6A/B-specific CD4+ T cell responses were found to be very low, and the CD8+ response was even lower. CMV-specific T cell responses were higher.

After stimulation of the samples with the HHV-6 and CMV lysates, the frequency of late-differentiated HHV-6-specific CD4+ cells was significantly lower than the frequency of late-differentiated CMV-specific cells, while the frequency of HHV-6-specific CD4+ T cells that were less differentiated was found to be higher than that of CMV-specific cells. Similarly, HHV-6-specific CD8+ T cells also tended to be less differentiated. A higher frequency of HHV-6A and HHV-6B-specific suppressive effector Tregs (eTregs) was observed, compared to the frequency of CMV-specific eTregs. A negative correlation was detected between virus-specific eTreg and effector T cell response frequencies, for both viruses, which may be due to the suppressive effects of Tregs that limit specific conventional effector/memory T cell responses.

In addition, HHV-6 was associated with higher IL-10 production and lower TNF-alpha production compared to CMV.

HHV-6A and HHV-6B modulate the immune system using a variety of strategies. As is the case for several other strategies, induction of Tregs likely aids HHV-6 in avoiding detection and destruction by the immune system, which allows it to establish persistent infection.

HHV-6(B) has been associated with a severe condition known as DIHS/DRESS (Descamps 2014, Mine 2014), which is characterized by initial Treg expansion. Subsequently, during resolution, Treg numbers fall dramatically, which may be involved in development of autoimmune conditions during this time (Takahashi 2009).

Monitoring these T cell responses over time in patients, such as DIHS/DRESS patients, with active HHV-6 infection could provide clinically relevant information for practitioners. The authors of the paper note that the accumulation of late-differentiated memory CMV-specific T cells is associated with impaired immunity and contributes to the immune risk profile in elders; further investigation could help determine whether HHV-6 might also be involved in the immune risk profile of older adults.

Find the full paper here: Fastenackels 2019.