Beyond T-cell subsets: stemness and adaptation redefining immunity and immunotherapy.

Abstract

T cells often acquire diverse phenotypes and functional states following activation. CD4⁺ T cells are traditionally classified into distinct effector subsets, such as Th1, Th2, Th17, and Tfh, on the basis of their cytokine profiles and functional roles. While this framework has advanced our understanding of adaptive immunity, it has limitations in explaining the persistence of T-cell responses in settings of autoimmunity and transplant rejection, in contrast to its limited efficacy in cancer. Moving beyond this subset-based framework, recent studies have revealed that stemness and adaptation are fundamental to CD4⁺ T-cell fate and function. Central to this new understanding is the TCF1⁺ stem-like CD4⁺ T-cell population, which emerges early after activation and serves as a reservoir for effector differentiation. These cells dynamically integrate environmental cues to direct effector differentiation and shape functional outcomes at target tissue sites, a process we define as clonal adaptation. By balancing self-renewal with effector differentiation, stem-like CD4⁺ T cells continue to replenish short-lived effector cells to sustain autoimmunity, transplant rejection, chronic infections, and allergic diseases. However, under tolerogenic conditions or within the tumor microenvironment, these cells often fail to differentiate into effectors, instead entering dysfunctional states or regulatory T-cell differentiation. Targeting stem-like CD4⁺ T cells offers great therapeutic potential: disrupting their persistence could mitigate autoimmune pathology and transplant rejection, whereas enhancing their effector capacity could improve antitumor immunity.