title: The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses.
abstract: Memory CD8 T cells provide protection to immune hosts by eliminating pathogen-infected cells during re-infection. While parameters influencing the generation of primary (1°) CD8 T cells are well established, the factors controlling the development of secondary (2°) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2° memory (M) CD8 T cells. We observed that the time at which 1° M CD8 T cells enter into immune response impacts their fate and differentiation into 2° M CD8 T cells. Late-entry of 1° M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2° effector CD8 T cells, but also influenced the ability of 2° M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1° M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2° effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2° CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2° CD8 T cell responses. Thus, our data suggest that the process of 1° M to 2° M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches.
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Shaniya H
authors.initials: SH
authors.lastname: Khan
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Martin
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Starbeck-Miller
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America; Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America; Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America; Department of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D015151:Immunoblotting; D007156:Immunologic Memory / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors
chemical_list: D007376:Interleukin-2