Harnessing the homeostatic proliferation capacity of memory CD8+ T cells to restore immune memory after radiation exposure 2253074

Abstract

Abstract Introduction While lymphopenia elicits vigorous homeostatic proliferation and memory phenotype acquisition among naive CD8+ T cells, its impact on pre-existing memory CD8+ T (TMEM) cells remains unclear. We sought to define the T cell—intrinsic and —extrinsic factors governing the homeostatic proliferation of TMEM cells following radiation-induced lymphopenia and to assess whether adoptive transfer of cryopreserved TMEM cells could restore CD8+ T cell-mediated immune memory after acute radiation-induced lymphoablation. Methods Specific pathogen free mice were subject to 0 or 5Gy of whole-body irradiation (WBI) followed by co-adoptive transfer of equal numbers of allelically-distinct memory P14 cells of different age. The numbers, tissue distribution and phenotype of the donor cells were longitudinally analyzed. In parallel, LCMV-experienced P14 chimeric mice that had recently undergone WBI were given varying doses of cryopreserved Thy1-disparate memory P14 cells to compare the homeostatic proliferation and antigen-dependent functionality between WBI-surviving and post-WBI transferred P14 TMEM cell. Results Post-WBI transferred P14 TMEM cells numerically expanded in lymphopenic hosts and maintained stable numbers over time, with late P14 TMEM cells displaying greater proliferation capacity than early P14 TMEM cells. The extent of proliferation was directly proportional to the number of input cells and the duration of lymphopenia in the recipients. In addition to populating blood and secondary lymphoid organs, the progeny also resided in the brain tissue. Compared with WBI-surviving P14 TMEM cells, post-WBI transferred P14 TMEM cells exhibited enhanced homeostatic proliferation and secondary expansion upon antigen re-encounter while maintaining similar cytokine production capacity. Conclusion Transfer of small numbers of radiation-inexperienced TMEM cells into recently irradiated hosts partially restores both the number and functionality of the TMEM compartment otherwise depleted by radiation exposure. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)