Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells

Area of Science:

• Immunology
• Cellular Biology

Background:

• CD28 and NKG2D are co-stimulatory receptors on human CD8+ T cells.
• Their distinct roles in different CD8+ T cell subsets remain unclear.

Purpose of the Study:

• To investigate the differential expression and function of CD28 and NKG2D in human peripheral blood and lung-derived CD8+ T cell subsets.
• To elucidate the specific co-stimulatory roles of CD28 and NKG2D in effector versus naïve/memory CD8+ T cells.

Main Methods:

• Analysis of CD28 and NKG2D expression on human peripheral blood mononuclear cell (PBMC)-derived and lung-resident CD8+ T cells.
• Functional assessment of co-stimulation via CD28 and NKG2D on cytokine production (IFN-γ, TNF-α, IL-2) in distinct CD8+ T cell subsets.
• Evaluation of MICA ligand expression on tracheal epithelial cells.

Main Results:

• CD28 expression was high on naïve/memory CD8+ T cells (CD28Hi) and low on effector CD8+ T cells (CD28Lo).
• NKG2D expression was comparable across all CD8+ T cell subsets.
• NKG2D co-stimulation boosted IFN-γ and TNF-α in CD28Lo effector cells but not in CD28Hi cells.
• CD28 co-stimulation was essential for IL-2 production, limited to CD28Hi cells.
• MICA was abundant on tracheal epithelial cells.

Conclusions:

• NKG2D provides significant co-stimulation to tissue-resident effector CD8+ T cells.
• Activating tumor or tissue-infiltrating effector CD8+ T cells requires both CD28 and NKG2D co-stimulation.
• Recall responses and vaccination strategies targeting naïve/memory CD8+ T cells necessitate CD28-mediated co-stimulation.