What is clonal anergy and how does it relate to peripheral tolerance?

• A. Anergy refers to deletion via apoptosis only in central lymphoid organs.
• B. Clonal anergy is functional inactivation of lymphocytes upon recognition of self-antigen without proper costimulation, contributing to peripheral tolerance.
• C. Anergy is rapid clonal expansion of self-reactive T cells.
• D. Anergy is a state of hyperreactivity to self-antigen.

Answer: (B)

Clonal anergy is a state of functional unresponsiveness in which a lymphocyte recognizes its specific antigen but does not receive the necessary second, costimulatory signal to become fully activated. In T cells, activation requires two signals: the TCR recognizing antigen-MHC (signal one) and a costimulatory cue (such as CD28 engagement with B7). When a self-antigen is encountered without this costimulation, the T cell fails to upregulate IL-2 and cannot proliferate or differentiates into effector cells. This keeps self-reactive cells in check in the peripheral tissues, forming a key part of peripheral tolerance. Central tolerance, by comparison, mainly removes self-reactive clones through deletion in primary lymphoid organs, but clonal anergy represents the peripheral mechanism of inactivation. The idea that anergy means rapid expansion or hyperreactivity, or that it equals deletion, does not fit with the actual role of anergy as a loss of responsiveness rather than an activation or deletion process.