How the immune system achieves self-nonself discrimination during adaptive immunity

Area of Science:

• Immunology
• Autoimmunity
• T cell biology

Background:

• Self-nonself discrimination is crucial for immune system function, preventing autoimmunity.
• Current models inadequately explain the complexities of immune tolerance and autoimmune disease development.
• T cell fate is influenced by interactions with antigen-presenting cells (APCs) in the thymus and periphery.

Purpose of the Study:

• To propose the Avidity Model of Self-Nonself Discrimination.
• To explain how T cell receptor (TCR) avidity, rather than just antigen structure, dictates immune responses.
• To provide a unified framework for understanding immunological disorders and autoimmune diseases.

Main Methods:

• Conceptual framework integrating central thymic selection and peripheral immune regulation.
• Analysis of T cell survival and fate based on TCR avidity with MHC/antigen peptides on APCs.
• Examination of peripheral T cell repertoire composition and its role in self-tolerance.

Main Results:

• High-avidity T cell clones recognizing self-antigens are deleted in the thymus, leaving intermediate and low-avidity clones.
• Intermediate-avidity self-reactive T cells in the periphery pose a risk for developing autoimmune diseases.
• Peripheral downregulation of intermediate-avidity T cells, including self-reactive ones, can control autoimmunity without compromising anti-infection immunity.

Conclusions:

• The Avidity Model posits that immune tolerance is achieved by modulating T cell activation avidity.
• Peripheral immune regulation, exemplified by Qa-1-restricted CD8(+) T cells, selectively targets intermediate-avidity T cells.
• This model offers a novel perspective on autoimmune disease development and control, unifying disparate immunological concepts.