Learning the rules of tissue-specific immunity could pave the way to a more promising future

Image by Masum Ali from Pixabay

New discoveries in immunology have been driven by the recent push to increase vaccine efficacy, revealing several innovative approaches with unrealized medicinal possibilities. Tissue-resident memory T cells (TRM cells) are the subject of a rapidly expanding field of study because of the long-term immunity they give against infections that target certain organs and tissues.

Researchers from the University of California San Diego School of Medicine released a new study on TRM cell biology in the gut on December 28, 2022 in Immunity. Their findings have the potential to lead to a new generation of precision treatments against infection, cancer, and autoimmune disease.

Memory T cells are left behind by the immune system after an infection. These cells keep a molecular memory of the pathogen and are activated to its reappearance. Some memory T cells are intended to travel throughout the body via the bloodstream, protecting the entire organism from infection, while others are located in different organs and are programmed to combat only the pathogens that threaten that particular organ. TRM cells have the potential to offer lifelong protection at the target tissue, but their overactivation can contribute to autoimmune disorders.

According to senior author and UC San Diego School of Medicine professor John T. Chang, MD, TRM cells are the initial defenders, right at the front lines of infection.  Most of the vaccinations aim to establish systemic immunity, but higher protection may be achieved by targeting the tissue-specific cells that come into contact with the pathogen directly.

Improving TRM cell function in the intestines may be the most effective way to treat pathogenic gut microbes, whereas improving TRM cell function in the nose and lungs may be the most effective way to combat a respiratory virus. Thus, the aim is to create therapies that can either increase TRM cell development and maintenance or, in the case of autoimmune illness, eliminate immune cells by altering the same pathways.

However, there is still much that has to be learned about what aids TRM cell formation and survival, and it’s possible that the criteria are very different for different types of tissues.

The researchers conducted a series of studies on mice to describe TRM cells from four distinct regions of the gastrointestinal tract: the small intestine, the colon, the ileum, and the jejunum.

In addition to substantial transcriptional, epigenetic, and functional heterogeneity, the analysis demonstrate that TRM cells in each tissue type expressed cytokines and granzymes in unique patterns. That is to say, identical immune cells from various regions of the gut appeared to have significantly different molecular compositions, functions, and reliance on chemical stimuli.

Further supporting this notion is the observation that Eomesodermin (Eomes), a transcriptional factor known to influence TRM cell growth, is required at varying levels by each cell group. Previous findings from the skin, liver, and kidney suggested that Eomes inhibited TRM cells, but the current trials showed the opposite to be true in the small intestine. There, Eomes had an unexpected function in TRM cell viability. But, the colon was an exception, demonstrating that context matters even inside the digestive tract.

Defining the principles for TRM cell development and maintenance in other tissues and revealing what drives their specialization will continue to be a focus of future research. The authors propose, for instance, that TRM cells have unique requirements because of the differences in the microbiome of the small intestine and the colon; hence, microbiome manipulation may be an additional strategy for regulating gut immune cells.

The researchers want to be thinking about vaccinations and other therapies that are tailored to the individual demands of each organ. The best immune responses against disease can be provided by understanding the requirements of each tissue type for the development and maintenance of TRM cells.


Lin, Y. H., Duong, H. G., Limary, A. E., Kim, E. S., Hsu, P., Patel, S. A., Wong, W. H., Indralingam, C. S., Liu, Y. C., Yao, P., Chiang, N. R., Vandenburgh, S. A., Anderson, T. R., Olvera, J. G., Ferry, A., Takehara, K. K., Jin, W., Tsai, M. S., Yeo, G. W., Goldrath, A. W., … Chang, J. T. (2022). Small intestine and colon tissue-resident memory CD8+ T cells exhibit molecular heterogeneity and differential dependence on Eomes. Immunity, S1074-7613(22)00643-4. Advance online publication. https://doi.org/10.1016/j.immuni.2022.12.007