Cd74, also known as the MHC class II invariant chain (Ii), is a non-polymorphic type II transmembrane glycoprotein. It serves as a chaperone for MHC class II molecules, playing a crucial role in antigen presentation. Additionally, Cd74 is a cell-membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopachrome tautomerase (D-DT/MIF-2) and bacterial proteins. The activation of the Cd74/CD44 receptor complex can trigger multiple intracellular signal pathways, such as the extracellular signal-regulated kinase (ERK) 1 and 2, the PI3K-Akt signal transduction cascade, NFκB, and the AMP-activated protein kinase (AMPK) pathway. Cd74 is involved in many physiological and pathological processes, including T-cell and B-cell development, dendritic cell motility, macrophage inflammation, and thymic selection [1].

In tumor-infiltrating regulatory T cells (Tregs), genetic deletion of Cd74 in human primary Tregs shows that Cd74KO Tregs have major defects in actin cytoskeleton and intracellular organelle organization. Intratumoral Cd74KO Tregs display decreased activation, reduced Foxp3 expression, and lower accumulation in tumors, leading to accelerated tumor rejection in female mouse pre-clinical models. This indicates that Cd74 is a specific regulator of tumor-infiltrating Tregs [2]. In cervical cancer, blocking tumor-associated macrophage-derived Cd74 enhanced macrophage phagocytosis, decreased cervical cancer cell viability in vitro and in vivo, thus improving the efficacy of neoadjuvant chemotherapy combined with PD-1 blockade [3]. In hepatocellular carcinoma (HCC), CD74 was highly expressed. Both copy number variations in CD74 and its expression patterns affected immune cell infiltration levels, and high CD74 expression was associated with better outcomes after immunotherapy [4].

In conclusion, Cd74 is essential for antigen presentation and acts as a receptor for multiple proteins, regulating various cellular processes. Gene knockout models, especially in the context of tumors, have revealed its role in modulating immune cell functions, such as in Tregs and macrophages, which are crucial for tumor development and response to therapy. Understanding Cd74's functions through these models provides insights into disease mechanisms and potential therapeutic targets in cancer and other immune-related diseases.

References:

1. Su, Huiting, Na, Ning, Zhang, Xiaodong, Zhao, Yong. 2016. The biological function and significance of CD74 in immune diseases. In Inflammation research : official journal of the European Histamine Research Society ... [et al.], 66, 209-216. doi:10.1007/s00011-016-0995-1. https://pubmed.ncbi.nlm.nih.gov/27752708/

2. Bonnin, Elisa, Rodrigo Riestra, Maria, Marziali, Federico, Tosello Boari, Jimena, Piaggio, Eliane. 2024. CD74 supports accumulation and function of regulatory T cells in tumors. In Nature communications, 15, 3749. doi:10.1038/s41467-024-47981-3. https://pubmed.ncbi.nlm.nih.gov/38702311/

3. Wang, Zixiang, Wang, Bingyu, Feng, Yuan, Zhang, Youzhong, Cui, Baoxia. 2024. Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer. In Journal for immunotherapy of cancer, 12, . doi:10.1136/jitc-2024-009024. https://pubmed.ncbi.nlm.nih.gov/39107132/

4. Cheng, Jianghong, Li, Junyang, Jiang, Xinjie, Chen, Shuai, Wang, Yang. 2024. CD74 facilitates immunotherapy response by shaping the tumor microenvironment of hepatocellular carcinoma. In Molecular medicine (Cambridge, Mass.), 30, 116. doi:10.1186/s10020-024-00884-x. https://pubmed.ncbi.nlm.nih.gov/39118044/