Establishment and Maintenance of the Human Nalve CD4+ T-Cell Compartment

The naive CD4(+) T-cell compartment is considered essential to guarantee immune competence throughout life. Its replenishment with naive cells with broad diverse receptor repertoire, albeit with reduced self-reactivity, is ensured by the thymus. Nevertheless, cumulative data support a major requirement of post-thymic proliferation both for the establishment of the human peripheral naive compartment during the accelerated somatic growth of childhood, as well as for its lifelong maintenance. Additionally, a dynamic equilibrium is operating at the cell level to fine-tune the T-cell receptor threshold to activation and survival cues, in order to counteract the continuous naive cell loss by death or conversion into memory/effector cells. The main players in these processes are low-affinity self-peptide/MHC and cytokines, particularly IL-7. Moreover, although naive CD4+ T-cells are usually seen as a homogeneous population regarding stage of maturation and cell differentiation, increasing evidence points to a variety of phenotypic and functional subsets with distinct homeostatic requirements. The paradigm of cells committed to a distinct lineage in the thymus are the naive regulatory T-cells, but other functional subpopulations have been identified based on their time span after thymic egress, phenotypic markers, such as CD31, or cytokine production, namely IL-8. Understanding the regulation of these processes is of utmost importance to promote immune reconstitution in several clinical settings, namely transplantation, persistent infections, and aging. In this mini review, we provide an overview of the mechanisms underlying human naive CD4(+) T-cell homeostasis, combining clinical data, experimental studies, and modeling approaches.