Fig. 1. Development of CD4 T cells and functional diversity of CD4 subsets in immunity.

CD4⁺ T cells are T lymphocytes that express T cell receptors (TCRs) recognising peptide antigens presented in the context of Class II major histocompatibility complex (MHC II) molecules. CD4⁺ T cells express the TCR co-receptor CD4, which binds to the β2 domain of MHC II and facilitates TCR engagement with peptide-MHC II complexes on antigen-presenting cells [111]. During thymic development, the cell fate of developing thymocytes is decided by their TCR affinity for self-peptide-MHC complexes presented by thymic epithelial cells. Thymocytes that have little to no affinity for self-peptide do not initiate activating signals from their TCR complexes and thus die by neglect. Conversely, thymocytes with high self-reactivity are negatively selected and deleted by apoptosis. Thymocytes with intermediate TCR affinities below the negative selection threshold receive positive selection via activating TCR signals and complete thymic maturation as naïve conventional T cells (T_H0). Some thymocytes with moderately high affinities to self-antigen are redirected into the regulatory T cell (Treg) developmental pathway, where they acquire immunosuppressive function to regulate tissue homoeostasis and resolution of immune responses [53, 112]. Upon receiving cues from the cytokine milieu together with TCR activation, naive CD4⁺ T cells upregulate expression of key transcription factors regulating subset differentiation, which in turn drive the expression of major effector cytokines associated with each particular subtype [113, 114]. Key transcription factors and cytokines involved are indicated for individual subtypes. CD4⁺ T cells augment the development of the CTL response [21, 24] and are required for the development of CD8⁺ T cell immunity (reviewed extensively here [115]) in their role as central co-ordinators of adaptive immunity. Unlike CD8⁺ T cells, whose primary function is to mediate cell contact-dependent cytotoxicity of infected or malignant cells, CD4⁺ T cells exhibit a diverse repertoire of effector functions and exhibit considerable phenotypic plasticity and heterogeneity depending on local context and microenvironment [113, 114]. CD4⁺ T cells activated in the periphery can also differentiate into induced Tregs (iTregs), which are able to mediate immunosuppression similar to thymic Tregs (tTregs).