Publication Review – Tissues, Not Blood, Are Where Immune Cells Function

Digital Pathology - Tissue Histology


Donna L. Farber Nature 593, 506-509 (2021)


Review by Suchandrima Bhowmik


Researchers have found that certain immune cells are not found in the blood. Some immune cells such as the macrophages are derived directly from the progenitor cells to mature in tissues such as the liver, lungs, and spleen. Other immune cells such as memory T cells develop from activated T cells which migrate to specific tissues where they reside for a long duration.

The COVID-19 pandemic has revealed major gaps our in understanding of the human immune system, one of those being the nature of the reactions taking place in the tissues. Researchers from the University of Columbia led by Donna L. Farber found something surprising during the early stages of the ongoing COVID-19 pandemic. This was observed in patients who were under ventilation after being infected by SARS-CoV-2.

Daily rinses of the plastic tube that was placed in their windpipe showed presence of immune cells from the airway. These airway samples were different from the ones obtained from blood. The airway samples indicated production of high cytokine levels with high numbers of T cells, whereas the blood samples showed higher numbers of monocytes.

Investigation using mouse models

Mouse models for the study of autoimmunity, cancer, infection, and inflammatory diseases have proved to be of considerable importance in elucidating the functioning of the immune system. Mouse studies mostly involve site-specific studies of the affected organs and the associated lymph nodes.

For example, a respiratory infection with a virus leads to the migration of dendritic cells from the lungs to the adjacent lymph nodes. At the lymph nodes they cause activation of CD4+ T cells that in turn leads to differentiation of B cells and the production of CD8+ T cells. These cells then migrate to the lungs where they kill the infected cells and prevent further spread of the virus. After the infection is cleared a small proportion of the memory T cells and B cells persist in the tissue for future protection against the same virus.

Mouse studies have also shown that in case of site-specific viruses such as human papillomavirus and influenza virus, the memory T cells are ‘tissue resident’. This would suggest that memory T cells are found in the skin for cutaneous pathogens, in the lungs for respiratory pathogens, and in the reproductive tract for genital infections.

In humans, it is practically impossible to determine and follow an immune response from the start of an infection to the development of immunological memory.  However, the blood of humans contains all major lineages of immune cells including circulating antibodies as well as cytokines and this approach has been helpful in tracking COVID-19 infection and vaccination.

Bridging the gap between tissue research and immune profiling

“Our work and that of others indicates that the composition of immune cells is distinct in different tissues, with tissue-specific variation in gene expression, metabolic pathways and functional regulation. Defining these properties could target therapies to tissue immune responses — but that requires first looking at the tissues,” said Donna L. Farber.

Tissue samples are normally collected from living individuals through routine medical procedures, such as biopsies and elective surgeries.

Donna L. Farber and her team of researchers set up a new type of tissue resource to obtain samples from organ donors. To obtain the samples they reached out to LiveOnNY, a non-profit organization in New York City. An on-call surgeon was kept ready to respond whenever a potential donor had died.

The surgeon carried out research with the tissues collected from different organs such as lungs, intestines, lymph nodes, bone marrow, thymus, skin, salivary glands, and tonsil. It has been found that linkage of tissue collection with the donation of organs is the best way to preserve the samples.

Technological advances help to pinpoint RNA transcript, protein content, as well as gene modification even for single cells. When these are combined with computational analyses it helps in the identification of immune cell composition, functional states, and lineages. This detailed immune profiling was found to play an important role in revealing immune signatures of infections as well as vaccines from flu to SARS-CoV-2.

“My team and others have compared distinct tissues in hundreds of individual donors to map the different types of innate and adaptive immune cell in each. Our ongoing studies include determining how tissue immune profiles correlate with factors such as sex and age,” said Donna L. Farber.


For the advancement of this research in human tissue, three important steps must be taken by the researchers, institutions, and funders. The first being an increased focus on ‘paired’ sampling. Both immunologists and clinicians should take advantage of opportunities for the simultaneous collection of blood and tissue samples. This helps to correlate immune parameters in the blood and tissue along with the disease and outcome.

The second step is the adaption of biobank collections. There are dozens of biobanks throughout the world that contain thousands of tissue samples, but these samples are not currently useful for immunologists. That situation could be improved if biobanks, along with preserving samples chemically for pathology, could also store frozen tissue and secretions so as to preserve the immune cells and soluble factors.

The third step is supporting and streamlining collaborations between immunologists and clinicians. Presently an immunologist needs to connect with clinicians on a case-by-case basis in order to acquire tissue samples for research. Joint projects could be established that would go beyond collection of samples. The emergence of SARS-CoV-2 has highlighted the need for the establishment of these types of collaborations to help resolve some of the more intractable questions in human immunology.



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