Unregulated antigen-presenting cell activation by T cells breaks self tolerance

Area of Science:

• Immunology
• T cell biology
• Self-tolerance mechanisms

Background:

• T regulatory cells (Tregs) are crucial for maintaining self-tolerance.
• Depletion of natural Tregs (nTregs) or transfer of naive T cells to Treg-deficient hosts leads to T cell proliferation.

Purpose of the Study:

• To investigate the nature of self-antigens driving T cell proliferation in the absence of nTregs.
• To elucidate the mechanisms underlying T cell activation and peripheral Treg (pTreg) formation in nTreg-deficient environments.

Main Methods:

• Experiments using mice raised in an antigen-free (AF) environment.
• Analysis of T cell proliferation and dendritic cell (DC) activation.
• In vitro co-culture of T cells and DCs.

Main Results:

• T cell proliferation in nTreg-deficient settings is directed towards self-ligands, not external antigens.
• Absence of nTregs increases B7 expression on DCs, enabling high-affinity naive CD4 T cells to respond.
• This interaction leads to DC activation, T cell proliferation, and pTreg generation.

Conclusions:

• Self-tolerance is maintained through the modulation of CD28 signaling by nTregs.
• The findings explain the effects of superagonistic CD28 antibodies and highlight the role of DCs in initiating anti-self responses when nTregs are absent.