Long-lived memory CD8+ T cells are programmed by prolonged antigen exposure and low levels of cellular activation.
CD8+ T cells play a crucial role in controlling intracellular pathogens. The level of memory CD8+ T cells developing after vaccination or infection influences the degree of T cell-mediated protection after secondary infection. We used defined animal models and infections/immunizations by replicating or non-replicating antigens to define on a molecular and cellular level in vivo the parameters that identify and shape long-lived CD8+ T cell memory. We show that the timing of antigen exposure during vaccination is key for the induction of long-lived T cell memory. Brief antigen exposure induced high numbers of effector cells but limited development of long-lived CD8+ memory T cells. In contrast, prolonged antigen exposure for up to 9 days induced similar numbers of effector T cells but additionally resulted in high levels of memory CD8+ T cells. Unexpectedly CD127 (IL-7Ralpha) expression on CD8+ T cells during the acute priming phase was a necessary but not sufficient requirement for entering the pool of long-lived antigen-independent memory CD8+ T cells. However, we provide strong evidence for the interpretation that programming of long-lived memory T cells was driven by low levels of transcription factor eomesodermin and protease inhibitor Spi2A as well as reduced phosphorylation of c-JUN.
Bachmann
Martin F
MF
Cytos Biotechnology AG, Zürich-Schlieren, Switzerland. martin.bachmann@cytos.com
Beerli
Roger R
RR
Agnellini
Paola
P
Wolint
Petra
P
Schwarz
Katrin
K
Oxenius
Annette
A
D000818:Animals; D000941:Antigens / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000276:immunology; D007156:Immunologic Memory; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D014612:Vaccines / Q000276:immunology*; D029867:Xenopus Proteins / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D000956:Antigens, Viral; C103223:EOMES protein, Xenopus; D020395:Receptors, Interleukin-7; C490400:Serpina3k protein, mouse; D015843:Serpins; D020825:T-Box Domain Proteins; D014612:Vaccines; D029867:Xenopus Proteins; C415350:interleukin-7 receptor, alpha chain; D048031:JNK Mitogen-Activated Protein Kinases