Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy

Area of Science:

• Immunology
• Cell Biology
• T cell activation

Background:

• T cell proliferation upon T cell receptor (TCR) ligation plus CD28 costimulation is heterogeneous.
• Some T cells fail to progress through the cell cycle and become anergic, even with IL-2.
• This IL-2-refractory anergy is distinct from IL-2-reversible anergy without CD28 costimulation.

Purpose of the Study:

• To investigate the roles of cell cycle progression and costimulatory signals (CD28/CTLA-4) in regulating T cell anergy.
• To understand the mechanisms underlying IL-2-refractory anergy and anergy avoidance.

Main Methods:

• Studied primary T cell responses with varying levels of TCR ligation, CD28 costimulation, and CTLA-4 signaling.
• Analyzed cell cycle progression and division status of T cells under different stimulatory conditions.
• Investigated the impact of CD28 costimulatory blockade on T cell proliferation and anergy induction.

Main Results:

• CD28 costimulation alone is insufficient to prevent anergy; cell cycle progression is essential for anergy avoidance.
• CTLA-4 signaling during the primary response induces a "division-arrest" anergy, contingent on failed cell cycle progression.
• T cell division alone does not guarantee anergy avoidance; clonal anergy can still occur even after multiple divisions under CD28 blockade.

Conclusions:

• Anergy avoidance in primary T cells is a multistep process requiring both CD28 costimulation and cell cycle progression.
• Anergy can be induced by CTLA-4 signaling combined with failed cell cycle progression, or by TCR ligation without CD28 costimulation.
• Successful T cell activation necessitates coordinated signals for proliferation and cell cycle entry to ensure a productive immune response.