CD4⁺CD8⁺ double-positive T cells in immune disorders and cancer: Prospects and hurdles in immunotherapy

CD4⁺ and CD8⁺ T cells play critical roles in both innate and adaptive immune responses, managing and modulating cellular immunity during immune diseases and cancer. Their well-established functions have led to significant clinical benefits. CD4⁺CD8⁺ double-positive (DP) T cells, a subset of the T cell population, have been identified in the blood and peripheral lymphoid tissues across various species. They have gained interest due to their involvement in immune disorders, inflammation, and cancer. Although mature DP T cells are present in healthy individuals and contribute to disease contexts, their molecular characteristics and pathophysiological roles remain debated. Notably, the number of DP T cells in the blood is higher in older adults compared to younger individuals, and these cells can stimulate inflammation and viral infections through increased secretion of interleukin (IL)-10, interferon gamma (IFN-γ), and transforming growth factor beta (TGF-β). In cancer, DP T cells have been observed to infiltrate cutaneous T cell lymphomas and are found in greater numbers in nodular lymphocyte predominant Hodgkin lymphoma, melanoma, hepatocellular carcinoma, and breast cancer. The higher prevalence of DP T cells in advanced cancers, coupled with their strong lytic activity and distinct cytokine profile, suggests that these cells may play a crucial role in modulating immune responses to cancer. This insight offers a potential new approach for enhancing the identification and selection of antigen-reactive T cells in immune-based treatments. This review provides a comprehensive overview of the origin, distribution, transcriptional regulation during developmental stages, and functions of DP T cells. A deeper understanding of the diversity and roles of DP T cells may pave the way for their development as a promising tool for immunotherapy in the management of immune disorders and metastatic cancers.