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Cell-to-Cell Interactions and Signals Involved in the Reconstitution of Peripheral CD8+ TCM and TEM Cell Pools

Public Library of Science
Publication Date
DOI: 10.1371/journal.pone.0017423
  • Research Article
  • Biology
  • Immunology
  • Immune Cells
  • T Cells
  • Immune System
  • Cytokines
  • Immunity
  • Immune Deficiency
  • Immune Suppression
  • Immunoregulation
  • Immune Response
  • Immunomodulation


We here describe novel aspects of CD8+ and CD4+ T cell subset interactions that may be clinically relevant and provide new tools for regulating the reconstitution of the peripheral CD8+ T cell pools in immune-deficient states. We show that the reconstitution capacity of transferred isolated naïve CD8+ T cells and their differentiation of effector functions is limited, but both dramatically increase upon the co-transfer of CD4+ T cells. This helper effect is complex and determined by multiple factors. It was directly correlated to the number of helper cells, required the continuous presence of the CD4+ T cells, dependent on host antigen-presenting cells (APCs) expressing CD40 and on the formation of CD4/CD8/APC cell clusters. By comparing the recovery of (CD44+CD62Lhigh) TCM and (CD44+CD62Llow) TEM CD8+ T cells, we found that the accumulation of TCM and TEM subsets is differentially regulated. TCM-cell accumulation depended mainly on type I interferons, interleukin (IL)-6, and IL-15, but was independent of CD4+ T-cell help. In contrast, TEM-cell expansion was mainly determined by CD4+ T-cell help and dependent on the expression of IL-2Rβ by CD8 cells, on IL-2 produced by CD4+ T-cells, on IL-15 and to a minor extent on IL-6.

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