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Differential expansion of T central memory precursor and effector subsets is regulated by division speed.

ABSTRACT: While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8⁺ T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment.

SUBMITTER: Kretschmer L

PROVIDER: S-EPMC6949285 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Differential expansion of T central memory precursor and effector subsets is regulated by division speed.

Kretschmer Lorenz L Flossdorf Michael M Mir Jonas J Cho Yi-Li YL Plambeck Marten M Treise Irina I Toska Albulena A Heinzel Susanne S Schiemann Matthias M Busch Dirk H DH Buchholz Veit R VR

Nature communications 20200108 1

While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8<sup>+</sup> T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that sl ...[more]

PMID: 31913278

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Project description:Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7R?-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7R?hi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.

Dataset Information

Differential expansion of T central memory precursor and effector subsets is regulated by division speed.

Publications

Differential expansion of T central memory precursor and effector subsets is regulated by division speed.

Similar Datasets

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