Figure 4.

Helpless dysfunction model. Upon priming of CD8⁺ T cells, a differentiation spectrum is formed, ranging from uncommitted memory precursors to terminally differentiated effector cells. In presence of CD4⁺ T cell help signals (left), the antigen-specific CD8⁺ T cell population attains higher differentiation states, with the majority of cells becoming terminally differentiated, short-lived effector CTLs. These helped CTLs clear the antigen source and die. When antigen wanes, memory precursor cells persist and form helped central (T_CM) and effector memory (T_EM) CD8⁺ T cells. In absence of help signals (right), antigen-specific CD8⁺ T cells undergo incomplete effector differentiation and terminally differentiated effector CTLs are lacking. Instead, predysfunctional effector CTLs are formed that are less committed (“memory-like”), i.e., have not fully unfolded their effector program and express coinhibitory receptors. In addition, formation of effector memory CD8⁺ T cells is impaired. As a result, antigen persists and continuous TCR stimulation of memory precursor cells drives their differentiation into predysfunctional CTLs that self-maintain or differentiate into terminally exhausted cells.