MUC1 Mucin: A Putative Regulatory (Checkpoint) Molecule of T Cells

Abstract

T lymphocytes are at the center of inducing an effective adaptive immune response and maintaining homeostasis. T cell responses are initiated through interactions between antigen presenting cells (APCs) and T cells. The type and strength of signals delivered through the T cell receptor (TCR) may modulate how the cells respond. The TCR-MHC (T cell receptor-major histocompatibility complex molecules) complex dictates the specificity, whereas co-stimulatory signals induced by interaction of various accessory cell surface molecules strengthen and optimize T cell responses. Multiple immune regulatory mechanisms brought about by co-inhibitory molecules expressed on T cells play a key role in orchestrating successful and non-damaging immunity. These co-inhibitory molecules are also referred to as initiators of immune check-points or co-inhibitory pathways. Knowledge of co-inhibitory pathways associated with activated T lymphocytes has allowed a better understanding of (a) the inflammatory and anti-inflammatory processes associated with infectious diseases and autoimmune diseases, and (b) mechanisms by which tumors evade immune attack. Many of these regulatory pathways are non-redundant and function in a highly concerted manner. Targeting them has provided effective approaches in treating cancer and autoimmune diseases. For this reason, it is valuable to identify any co-inhibitory molecules that affect these pathways. MUC1 mucin (CD227) has long been known to be expressed by epithelial cells and overexpressed by a multitude of adenocarcinomas. As long ago as 1998 we made a surprising discovery that MUC1 is also expressed by activated human T cells and we provided the first evidence of the role of MUC1 as a novel T cell regulator. Subsequent studies from different laboratories, as well as ours, supported an immuno-regulatory role of MUC1 in infections, inflammation, and autoimmunity that corroborated our original findings establishing MUC1 as a novel T cell regulatory molecule. In this article, we will discuss the experimental evidence supporting MUC1 as a putative regulatory molecule or a “checkpoint molecule” of T cells with implications as a novel biomarker and therapeutic target in chronic diseases such as autoimmunity, inflammation and cancer, and possibly infections.

Human Metapneumovirus Induces Mucin 19 Which Contributes to Viral Pathogenesis

“…The correlative observations in this work that Muc19 KO mice had less CD4+ T cells, less proinflammatory cytokines and less weight loss suggest that Muc19 could contribute to the HMPV-induced pathogenesis through a mechanism involving CD4+ T cells. In line with our findings, experimental evidence demonstrates that MUC1 inhibits the proliferation of human CD3+ T cells, which is attributed to its expression on both CD4+ and CD8+ T cells [ 35 , 36 ]. Similarly, additional work has demonstrated that MUC1 is expressed on the majority of T regulatory cells (CD4+/CD25+/Foxp3), which could provide co-stimulatory or co-inhibitory signals depending also on the number of accessory cell ratios present [ 37 ].…”

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

“…In particular, surface mucin genes, which play important roles in protecting epithelial cells and have been implicated in epithelial renewal and differentiation [ 31 ], were highly mutated in T47D-PR cells ( Table 2 ). These mucin genes were also reported to be involved in immune regulation [ 32 , 33 ].…”

Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

“…In particular, surface mucin genes, which play important roles in protecting epithelial cells and have been implicated in epithelial renewal and differentiation [30], were highly mutated in T47D-PR cells (Table 2). These mucin genes were also reported to be involved in immune regulation [31,32]. Visualization of GO revealing prominent immune process involvement in palbociclib-resistant cells GO enriched terms in the 107 genes with mutations in T47D or T47D-PR cells ( Supplementary Fig.…”