Biology subjects

Li, Z.-R. T.

Publications and source records attributed to Li, Z.-R. T..

3 recordsLinked to original sources

bioRxiv2022

Memory CD4 T cell subset organization in the female reproductive tract is regulated via the menstrual cycle through CCR5 signaling

Despite their importance for immunity against sexually transmitted infections (STIs), the composition of the female reproductive tract (FRT) memory CD4 T cell population in response to changes in the local tissue environment during the menstrual cycle remains poorly defined. Here we show that across humans, non-human primates (NHP), and mice, FRT CD4 T cells comprise distinct subsets corresponding to migratory memory (TMM) and resident memory (TRM) cells. TMM display tissue-itinerant trafficking characteristics, restricted FRT tissue distribution, with distinct transcriptional properties and effector responses to infection. CD4 T cell subset fluctuations synchronized with cycle-driven proinflammatory changes within the local tissue environment and oral administration of a CCR5 antagonist inhibited cycle phase-specific migratory T cell surveillance. This study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of memory T cell defense at the site of STI exposure. SummaryThe menstrual cycle regulates memory T cell surveillance.

immunology↗

bioRxiv2020

Quantifying memory CD8 T cell-mediated immune pressure on influenza A virus infection in vivo

The conservation of T cell epitopes in human influenza A virus has prompted the development of T cell-inducing influenza vaccines. However, the selection pressure mediated by memory CD8 T cells upon influenza virus has not been directly measured. Using a droplet digital PCR technique to distinguish wild-type and an epitope-mutant PR8 influenza viruses in vivo, this study quantifies the viral replicative fitness of a CD8 T cell-escaping mutation in the immunodominant influenza NP366-374 epitope in C57BL/6 (B6) mice under different settings of cellular immunity. Although this mutation does not result in a viral fitness defect in vitro or during the early stages of in vivo infection in naive B6 mice, it does confer a moderate but consistent advantage to the mutant virus following heterosubtypic challenge of HKx31-immunized mice. In addition, this advantage was maintained under increased MHC diversity but became more substantial when the breadth of epitope recognition is limited. Finally, we showed that lung-resident, but not circulating, memory CD8 T cells are the primary source of cellular immune pressure early during infection, prior to the induction of a secondary effector T cell response. Integrating the data with an established modeling framework, we show that the relatively modest immune pressure mediated by memory CD8 T cells is one of the important factors responsible for the conservation of CD8 T cell epitopes in influenza A viruses that circulate among humans. Thus, a T cell-inducing vaccine that generates lung-resident memory CD8 T cells covering a sufficient breadth of epitopes may transiently protect against severe pathology without driving the virus to rapidly evolve and escape. Author SummarySince the historic Spanish flu in 1918, influenza has caused several pandemics and become an important public health concern. The inactivated vaccines routinely used attempt to boost antibodies, which may not be as effective when antigenic mismatch happens and could drive the virus to evolve and escape due to their high immune pressure. In contrast, the ability of influenza-specific T cells to reduce pathology and the conservation of T-cell epitopes across subtypes have shed light on the development of universal vaccines. In this study, we assessed the CD8 T cell-mediated selection pressure on influenza virus in mouse using a digital PCR technique. Within mice that have influenza-specific systemic and lung-resident memory CD8 T cells established, we found the advantage conferred by an escaping mutation in one of the immunodominant epitopes is around 25%. This advantage becomes much greater when the cellular immunity focuses on the focal epitope, while it is delayed when only systemic cellular immunity is established. Combining the data with our previous modeling work, we conclude that the small selection pressure imposed by CD8 T cells can explain the overall conservation of CD8 T cell epitopes of influenza A virus in addition to functional constraint.

immunology↗

bioRxiv2018

Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

The high-degree conservation of CD8 T cell epitopes of influenza A virus (IAV) may allow T cell-inducing vaccines effective across different strains and subtypes. This conservation is not fully explained by functional constraint, since additional mutation(s) can compensate the replicative fitness loss of IAV escape-variant. Here, we propose three additional mechanisms that contribute to the conservation of CD8 T cell epitopes of IAV. First, influenza-specific CD8 T cells may protect predominantly against severe pathology rather than infection and may only have a modest effect on transmission. Second, polymorphism of human MHC-I gene restricts the advantage of an escape-variant to only a small fraction of human population, who carry the relevant MHC-I alleles. Finally, infection with CD8 T cell-escapevariants may result in compensatory increase in the responses to other epitopes of IAV. A combination of population genetics and epidemiological models is used to examine how the interplay between these mechanisms affects the rate of invasion of IAV escape-variants. We conclude that the invasion of an escape-variant will be very slow with a timescale of decades or longer, even if the escape-variant does not have a replicative fitness loss. Our results suggest T cell-inducing vaccines may not engender the rapid evolution of IAV and serve as a foundation for future modeling works on the long-term effectiveness and impacts of T cell-inducing influenza vaccines. (Word count: 221)\n\nImportanceUniversal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear to which extent the T cell-inducing vaccines will select for viruses that escape the T cell responses. Our mathematical models suggest how the nature of CD8 T cell protection contributes to the conservation of the CD8 T cell epitopes of influenza A virus. Also, it points out the essential biological parameters and questions that need addressing by future experimental works. (Word count: 91)

immunology↗