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

Md Rakibul Alam; Amos Olalekan Akinyemi; Jianlin Wang; Mithu Howlader; Mohammad Esfini Farahani; Maria Nur; Min Zhang; Lixiang Gu; Zhiguo Li

doi:10.1016/j.autrev.2025.103757

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

Autoimmun Rev. 2025 Jan 22:103757. doi: 10.1016/j.autrev.2025.103757. Online ahead of print.

Authors

Md Rakibul Alam¹, Amos Olalekan Akinyemi¹, Jianlin Wang¹, Mithu Howlader¹, Mohammad Esfini Farahani¹, Maria Nur¹, Min Zhang¹, Lixiang Gu¹, Zhiguo Li²

Affiliations

¹ Department of Toxicology and Cancer Biology, Collage of Medicine, University of Kentucky, Lexington, KY 40536, USA.
² Department of Toxicology and Cancer Biology, Collage of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: zhiguo.li@uky.edu.

PMID: 39855286
DOI: 10.1016/j.autrev.2025.103757

Abstract

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.

Keywords: CD4(+)CD8(+) double-positive T cells; Cancer; Immune disorder; Immunoregulation; Immunotherapy; T cell development; Transcriptional regulation.

Publication types

Review