An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation

Area of Science:

• Immunology
• Cellular Biology

Background:

• Memory CD8(+) T cells are crucial for rapid clearance of reinfections.
• The mechanisms driving rapid memory CD8(+) T cell proliferation upon antigen re-stimulation, exceeding naive T cell proliferation, remain unclear.
• Interleukin-15 (IL-15) and Interleukin-7 (IL-7) regulate slower homeostatic proliferation.

Purpose of the Study:

• To investigate the mechanisms underlying accelerated antigen-specific CD8(+) T cell proliferation during recall responses.
• To elucidate the role of cytokines in enhancing memory CD8(+) T cell proliferation upon secondary antigen challenge.

Main Methods:

• Ovalbumin (OVA) antigen was targeted to DEC-205(+) dendritic cells (DCs) with a CD40 maturation stimulus in vivo.
• Induction of functional memory CD8(+) T cells and assessment of their proliferation and cytokine production upon secondary challenge.
• Analysis of Interleukin-18 (IL-18) accumulation at the DC:T cell synapse and the role of Interferon-gamma (IFN-γ) receptors in IL-18 production.
• Evaluation of memory CD8(+) T cell expansion in IL-18 or IFN-γ-receptor 1 deficient mice.

Main Results:

• DC-targeted antigen induced memory CD8(+) T cells exhibiting rapid proliferation and multi-cytokine production (IFN-γ, IL-2, TNF-α).
• IL-18 accumulated at the DC:T cell synapse upon antigen presentation, and IFN-γ receptors were essential for augmenting DC IL-18 production.
• Mice lacking IL-18 or IFN-γ-receptor 1 displayed delayed memory CD8(+) T cell expansion.

Conclusions:

• A positive regulatory loop between IFN-γ and IL-18 signaling drives accelerated memory CD8(+) T cell proliferation during recall responses.
• This IFN-γ/IL-18 axis is critical for efficient expansion of memory CD8(+) T cells upon secondary antigen encounter mediated by dendritic cells.