Attenuation of Cytokine Responsiveness During T Cell Development and Differentiation

Abstract

Cytokines play critical roles during T cell development; however, it is unclear to what extent development is altered by the high levels of cytokines produced during immune responses. A potential mechanism to shield developing cells from cytokine influence is attenuation of cytokine signaling. Using intracellular staining and flow cytometry to detect cytokine-induced Stat phosphorylation, we analyzed the cytokine responsiveness of developmentally defined mouse T cells. We assessed CD4^–CD8^– (DN), CD4⁺CD8⁺ (DP), CD4⁺CD8^– (SP4), and CD4^–CD8⁺ (SP8) in the thymus, and CD4⁺CD44^lo (naive), CD4⁺CD44^hi (memory), CD8⁺CD44^lo (naive), and CD8⁺CD44^hi (memory) in the periphery for responsiveness to interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 10, IL-15, interferon-α (IFN-α), and IFN-γ. SP thymocytes responded to a wider range of cytokines than did the less mature DN and DP subpopulations. DP thymocytes were nonresponsive to all cytokines tested except for modest responses to IL-4 and IFN-α. Peripheral naive and memory T cells also displayed differential cytokine sensitivity. Memory T cells were less responsive to the proinflammatory cytokines IL-6 and IFN-γ when compared with naive T cells, and the memory CD4⁺ subset was less responsive to IL-4. In summary, developing thymocytes and memory T cells appear to be resistant to the influences of numerous cytokines produced during immune responses.