Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Complement system is a key part of innate immunity, primarily acting extracellularly.
• Complement component C3 processing into C3a and C3b was traditionally considered an extracellular process.

Purpose of the Study:

• To investigate intracellular complement C3 activation within T cells.
• To identify the mechanisms and functional significance of intracellular C3 processing in T cells.

Main Methods:

• Analysis of C3 processing in T cells using cathepsin L (CTSL).
• Detection of intracellular C3, CTSL, C3a, and C3b in resting and stimulated T cells.
• Examination of T cells from patients with autoimmune arthritis.

Main Results:

• T cell-expressed cathepsin L (CTSL) processes C3 into active fragments C3a and C3b intracellularly.
• Resting T cells contain intracellular C3 and CTSL, generating C3a for survival.
• T cell stimulation translocates this system to the cell surface, promoting cytokine production.
• T cells from autoimmune arthritis patients show hyperactive intracellular complement and interferon-γ.

Conclusions:

• Intracellular complement activation occurs in T cells, mediated by CTSL.
• This intracellular pathway is crucial for T cell homeostasis and inflammatory responses.
• CTSL inhibition can correct aberrant complement activation in autoimmune arthritis.
• Intracellular C3a generation may have broad physiological relevance across cell types.