Deciphering memory-like NK cell responses using polylox barcoding

• Applicant: Dr. Simon Grassmann
• Subject Area: Immunology
• Term: from 2020 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437340553

Adaptive-like immune responses of NK cells, mimicking features found in adaptive cells like CD8+ T cells, are found in both mice and humans. These responses are characterized by pathogen- or antigen-specificity, and the capacity of responding cells to form a stable pool of long-lived cells. However, so far only indirect evidence suggests that both primary expansion and long-term maintenance are mounted by the same NK cell clones. This clonal origin is a crucial prerequisite for ‘true’ immunological memory, which is why long-lived NK cell responses are so far only called ‘memory-like’ responses. The applicant has developed a technique which enables, for the first time, to study adaptive-like NK cell responses on a clonal level. In a productive collaboration with Nick Adams from the host laboratory of Joseph Sun the applicant has used this method to find that adaptive-like NK cells are capable of yet another feature of the adaptive immune system. NK cells appeared to undergo avidity-dependent clonal expansion driven by distinct expression levels of the antigen-receptor Ly49H itself (Grassmann et al. Immunity 2019; Adams et al. Immunity 2019).In this proposal the applicant will join the laboratory of Joseph Sun to study the capacity of NK cells to form ‘true’ immunological memory on a clonal level. To this end, a new method of single-cell fate mapping relying on polylox barcoding has partially been established in the laboratory by Nick Adams. In a first part, this approach will be used to answer the question whether NK cells form ‘true’ immunological memory. Possible outcomes are that i) NK cell memory-like responses are 'true' memory in the classical sense, ii) NK cell memory is 'true' but only certain NK cells are capable of it or iii) NK cell memory is not 'true' memory. Depending on these results subsequent experiments will serve to validate the result and dissect the exact mechanisms leading to memory-like responses by NK cells. The excellent methodology and expertise of the host laboratory with adaptive-like NK cells will grant the applicant the basis for a successful research project. The cutting-edge methods learned during this project will be the basis for starting his own work group in Germany upon return from this research fellowship.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Joseph C. Sun, Ph.D.