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We could show that non-cytolytic central memory precursors (CMPs) emerge early during the acute phase of chronic-latent murine Cytomegalovirus infection and then form the stem-cell-like basis of long-term immunological memory against this virus. Via continuous live cell imaging in vitro, we have identified critical connections between cell-cycle speed and T cell fate decisions. We found that CD8+ T cells, derived from a single naïve precursor, segregate into heritably slow and fast dividing branches that channel in vivo into the formation of slower-cycling but long-lived CMPs and quickly dividing but shorter-lived non-CMPs.

Recently, using single-cell RNA sequencing, combined with RNA-velocity analysis of in situ developmental dynamics during chronic-active Lymphocytic choriomeningitis virus infection, we identified a minute T cell subset that lies at the origin of all differentiation trajectories within the TCF1+ compartment of precursors of exhausted T (TPEX) cells. Single-cell adoptive transfer and in vivo fate-mapping show that stem-cell-like self-renewal and multipotency as well as the proliferative response to PD-1 checkpoint inhibition originate exclusively from this subset of T exhausted stem cells, which express CD62L and the transcription factor Myb, and not from the bulk of their CD62L-negative TPEX descendants. These together with our previous findings have broad implications for the development of immunotherapeutic strategies against chronic infection and cancer.

Dr. Veit Buchholz is a principal investigator at the Institute for Medical Microbiology, Immunology and Hygiene at the Technical University of Munich.

The Buchholz Lab investigates the development of immunological memory, starting out from single antigen-specific lymphocytes in vivo and in vitro. Thereby, breaking down adaptive immune responses into their most fundamental building blocks. In the past, this unique experimental approach of "single-cell fate-mapping" has shown that even physiological immune responses to infection do not harness the full protective potential available in every antigen-specific lymphocyte. The lab’s aim is to identify ‘stem-like’ T and NK cells that stand at the origin of all differentiation processes underlying lasting immunological memory in the context of acute and chronic infection, malignancy and autoimmune disease. By identifying key factors that regulate these stem-like lymphocytes, the lab aims to open up new avenues for effective vaccination, immunomodulation and immunotherapy.