Cheers to long-lived memory T cells after shingles!

From Dr. Kerry Laing and the Koelle lab, Vaccine and Infectious Disease Division

The varicella-zoster virus (VZV) causes shingles and is the same virus that causes chickenpox. After a person has chickenpox, the virus remains dormant in their nerve cells (neurons) for the rest of their lives. Several years or even decades after infection, the virus may reactivate to cause shingles, a painful and blistering rash on the skin. Shingles recurrence is extremely rare, suggesting local and site-specific immunity. One’s T cells are a critical component of the immune system during an infection. During an infection, some T cells leave the circulation and enter the infected tissues, where they remain after the virus has been cleared. It is these T cells that provide site-specific immunity and can be referred to as tissue-resident memory T cells (TRM). “Resident memory T cells play a major role in preventing infection/reinfection of tissues impacted by their target pathogen," said Dr. Kerry J Laing, a senior research scientist in the Dr. David Koelle lab in the Vaccine Infection Disease Division at Fred Hutch and the University of Washington. She continued, “they are known to be present in human skin, but it has been a challenge to prove that these cells are both antigen specific and persist in the absence of cognate antigen or ongoing inflammation.” In a recent publication in Nature Communications, Dr. Laing, Dr. Koelle and colleagues reported the long-term persistence of VZV-specific TRM in patient skin biopsies one year following VZV clearance. Dr. Laing stated that their study “confirms that VZV-specific T cells do remain in skin long-term in persons recovered from shingles when antigen is no longer detectable and systemic VZV-specific immunity has waned.”

To conduct the study, blood samples and skin biopsies were collected from 18 subjects with shingles over a one-year period. The authors used contralateral biopsies of the same subject as controls. Using real-time polymerase chain reaction (real-time PCR), the authors demonstrated that viral DNA on the skin surface at the rash site had dramatically decreased after 45 days and was undetectable one year after the rash first appeared. The frequency of VZV-specific CD4 T cells in blood was measured and found to decline with time. Additionally, they conducted neutralization assays and found that neutralizing antibody titers also decreased over time. Their findings support that VZV antigen was cleared from the skin and inflammatory process caused by VZV were no longer ongoing.

The authors then used cryosections of skin biopsies to examine the proteins expressed by T cells. A higher number of T cells were found in the healed rash site skin samples, which were positive for TRM markers (CD69 and CD103), compared to control skin. Since T cells come in different flavors, CD4 and CD8 T cells being the two primary types, the authors compared the specificity of both against VZV. Using proteomic-wide studies, they found that both CD4 and CD8 TRM cells were antigen-specific, and their detection remained local after one year following VZV clearance. Interestingly, CD4 TRM cells predominantly recognized VZV glycoproteins, while CD8 TRM cells recognized a tegument protein encoded by open reading frame 9 (ORF9). Their findings indicated that “the VZV-specific TRM are at higher levels in the skin site impacted by the shingles rash compared to other areas of skin or blood early after shingles and remain enriched after one year,” Dr. Laing explained. “This finding supports the notion that TRM have limited migration and have preference to stay localized in sites where they had encountered inflammation and antigen.”

Detection of TRM markers (CD69 and CD103) by immunofluorescence in cryosections of VZV-skin biopsies. CD3 was used as marker of T cells.
Detection of TRM markers (CD69 and CD103) by immunofluorescence in cryosections of VZV-skin biopsies. CD3 was used as marker of T cells. Image taken from article

Dr. Laing explained that “precise location of TRM is essential to optimal control of infections,” however, it “raises a challenge to designing vaccines that specifically target T cells to appropriate tissues. Can a vaccine even generate a TRM in the right tissue in the absence of inflammation? Do enough vaccine-educated T cells have future potential to rapidly home to the appropriate tissue and stay there when their target pathogen makes its appearance? What are the optimal conditions needed to make a skin TRM?” Going forward, Dr. Laing is interested in “looking at the functions of skin TRM in the context of shingles or zoster vaccination in adults of various ages, to gain insight into some of these unanswered questions.”

This worked was supported by the National Institutes of Health.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member David Koelle contributed to this work.

Laing KJ, Ouwendijk WJD, Campbell VL, McClurkan CL, Mortazavi S, , Elder Waters M, Krist MP, Tu R, Nguyen N, Basu K, Miao C, Schmid DS, Johnston C, Verjans G, Koelle DM. 2022. Selective retention of virus-specific tissue-resident T cells in healed skin after recovery from herpes zoster. Nat Commun. 13(1):6957.