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

摘要

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⁺CD62L^high) TCM and (CD44⁺CD62L^low) 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.