How to learn about the differentiation states and functions of T cells from different species
Your immune system protects you from severe diseases by fighting pathogenic germs. These battles are carried out by the different types of white blood cells, such as B and T cells. In particular, CD8 T cells are specialized in the killing of infected cells and as such are nicknamed ‘killer’ T cell. They can detect infected cells and tumor cells in our body and eliminate them. Activation lets T cells develop into so-called memory T cells that protect us long-term from the pathogen. Vaccinations actively induce this process and use it to provide protection.
During an immune response T cells with different specializations are necessary. Which of these states are formed will determine how the immune system will fight an infection for instance. Some T cells live longer, others proliferate, some make more cytokines, and others can kill better. This functional diversity is regulated by T cell differentiation. The different T cell states are also connected to the clinical outcomes of interventions such as adoptive T cell therapy, and transplantation. Tools to precisely determine T cell differentiation states are therefore of clinical relevance when T cells contribute to immune control and/or disease.
Researchers from CMM have performed a meticulous study of the transitions between CD8+ T cell differentiation states. High detailed analysis showed a gradual, not step-wise, process. However, the currently used markers did not reflect this graded nature of CD8+ T cell differentiation. The researchers found that the expression level of the chemokine receptor CX3CR1 predicts the skills of the individual T cells. Importantly, CX3CR1 expression levels identifies functionally comparable T cell states in mice and humans. The resulting article was recently published in the journal Immunity.
“Human and mouse T cell immunology have been somewhat separate worlds. It was difficult to know which T cell subsets in humans corresponded to which T cell subset in mice, because although we gave the subsets the same names in both species (for example ‘effector memory’), the subsets were defined by completely different molecules. We wanted to find a common language between human and mouse T cell immunology so that it becomes possible to translate and interpret T cell properties (‘skills’) from one species to another”, says CMM Team Leader Carmen Gerlach, principal investigator and last author of the study.
The analyses revealed that graded expression of the chemokine receptor CX3CR1 mirrored the CD8+ T cell differentiation gradient and the corresponding T cell skills in a way that was comparable in humans and mice. Measuring the CX3CR1 expression gradient by flow cytometry is convenient and can be easily applied in clinical and fundamental science studies. Thus, measuring graded CX3CR1 expression provides a strategy to translate the behavior of distinct T cell differentiation states across species.
“The chemokine receptor CX3CR1 serves as an easy to use and effective measure to translate from one into the other species. Very similar to how the Rosetta Stone enabled translation between two different languages. We envision that our discovery allows for the deciphering of novel immunological mechanisms”, says Anthonie Zwijnenburg, PhD student in the Gerlach lab and first author.
First author Anthonie Zwijnenburg led the study and performed the largest part of it. Carmen Gerlach is the principal investigator. Second author Jyoti Pokharel, PhD student in the Gerlach lab, also made a substantial contribution to the study. All members of the Gerlach lab at CMM have contributed to the study in some way. CMM contributors beyond the Gerlach lab were Elena Hoffer and Liv from the Eidsmo lab.
The study was performed in collaboration with other researchers from Karolinska Institutet, some of which are also affiliated with Umeå University and the University of Copenhagen.
Funding was obtained from the Swedish Research Council, Ragnar Söderbergs Stiftelse, Jeansson Stiftelser, the Knut and Alice Wallenberg Foundation, Cancerfonden, Karolinska Institutet, the Marianne and Marcus Wallenberg Foundation, Region Stockholm, the Center for Innovative Medicine and Psoriasisfonden.
Zwijnenburg AJ, Pokharel J, Varnaitė R, Zheng W, Hoffer E, Shryki I, Comet NR, Ehrström M, Gredmark-Russ S, Eidsmo L, Gerlach C. Immunity. 2023 Jul 14:S1074-7613(23)00282-0. doi: 10.1016/j.immuni.2023.06.025. Online ahead of print.PMID: 37490909