CD4⁺ T cells as Orchestrators of Immune Responses

CD4⁺ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4⁺ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4⁺ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach

Thymic development of T cells clearly distinguishes two different fates for the MHC class II-restricted CD4⁺ T helper (Th) and the MHC class I-restricted CD8⁺ cytotoxic T cell lineages. However, it is now widely believed that CD4⁺ T cells can also exert cytolytic activity beside the helper function, as demonstrated by in vitro and in vivo evidence. The main role of CD4⁺ T cells is to indirectly orchestrate the immune response by differentiating into distinct Th cell populations. These subsets are characterized by specific differentiation signals, expression of distinct master transcription factors, secretion of signature cytokines, and specific functions. The first functional diversification proposed, identified, and separated Th1 from Th2. Th1 cells are induced by interleukin (IL)-12, express T-bet, and target intracellular pathogens through the release of interferon (IFN)-γ. Conversely, Th2 lymphocytes are stimulated by IL-4, are characterized by GATA-3 expression and IL-4 production, and play a critical role in fighting extracellular parasites. During the years, several other functionally distinct subsets of helper CD4⁺ T cells have been identified and characterized. Th17 cells control fungi and extracellular bacteria through the release of IL-17 and IL-22.

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Alex John
Editorial Assistant
Clinical Toxicology