How to Train Your T Cell(s): The Hidden World
Almost immediately after birth, the microbial communities on and in the human body begin to establish. The surface of human skin is dry, salty, and is a low pH (~5) environment composed of dead skin cells formerly called keratinocytes. It is also tumultuous, since frequent winds and abrasive surfaces slough off dead skin cells. As a consequence, the skin microbiota doesn’t live on the outer surface of the skin. Instead, they live below the dead cells, past a layer of dying cells, and within the layer of still-living keratinocytes (image 1).
Understanding how our immune system responds to this migration is a longstanding question that researchers have only recently begun to address.
The relationships between microbe and human are often thought of in two ways: either pathogenic invaders or friendly symbionts. Prior immunological research has focused on the first relationship, but researchers are now realizing that the majority of microbes encountered by our immune system are members of our microbiomes, not pathogens. Such interactions lead to the presence of more than 20 billion lymphocytes (white blood cells) in healthy human skin whose microbial targets are unknown. Presumably, these lymphocytes are responding to the skin microbiota, but how do they know which microbes are friends and which are foes?
Understanding interactions between T cell lymphocytes and commensal microbes is the cornerstone of Dr. Yasmine Belkaid’s research. Dr. Belkaid is a researcher at the National Institutes of Health. Her focus is how the skin microbiome influences the immune system during health, and has uncovered a relationship that increases immune adaptability and function.
A prominent member of the healthy skin microbiome, and a focus of Dr. Belkaid’s research, is the gram-positive bacteria Staphylococcus epidermidis (S. epi). Upon the arrival of S. epi in the skin, dendritic cells (a lymphocyte) that reside in the skin sample the array of proteins and molecules secreted by S. epi. The dendritic cells then migrate to the lymph nodes where other lymphocytes reside.
To communicate the type of pathogen present and trigger an appropriate response, foreign peptides are selected from the sample, processed, and then presented to naive T cells by the dendritic cells using a type of protein called MHC. In the context of bacterial pathogens, class II MHCs are used and the resulting peptide-MHC II complexes are recognized by a T cell in the CD4 subset. If it were a viral or intracellular bacterial pathogen, the selected and processed peptide would be presented on MHC class I proteins, which would recruit T cells from the CD8 subset.
However, Dr. Belkaid's research in mice has found that commensal bacterial peptides, like those of S.epi, are instead presented using “non-classical” MHC class I proteins that recruit and train T cells from the CD8 subset. The genes encoding these “non-classical” MHC proteins have been conserved since mice and human lineages split, about 50 million years ago, while the “classic” MHC I genes have evolved significantly since then. This suggests an ancient relationship between commensals and the immune systems of both mice and humans that differs dramatically from the modern relationship with pathogens.
Once a T cell is trained to follow a certain inflammatory path, it typically cannot trigger different inflammation responses. For example, a CD8 T cell ‘trained’ to release IFNg that activates the JAK-STAT pathway, cannot be ‘retrained’ to release IL-17A to activate the NF-kB pathway, each of which has a different inflammatory outcome. Surprisingly, Dr. Belkaid’s research has found that commensal-specific CD8 T cells can switch from its initial inflammatory response to another when in the presence of both bacteria and inflammatory cytokines, an unusual trait in antigen-targeting T cells. So after their activation and training, the S.epi-specific CD8 T cells migrate to the skin and patrol through the layer of skin below the keratinocytes where they have the ability to flexibly respond to tissue damage (image 2).
The exact roles for these S.epi-specific T cells in the skin aren’t completely understood. Though Dr. Belkin’s research has found that these T cells express more genes related to tissue repair. This factor may enhance the ability of S.epi-specific T cells, keratinocytes, and S.epi to work in concert and protect the skin from invasive pathogens (e.g., S. aureus), cancer, and promote wound healing.
Living keratinocytes produce negatively-charged anti-microbial peptides that S.epi survives by virtue of its positively-charged cell wall. This adaptation allows S.epi to claim a niche in the skin environment which it protects by producing its own suite of antimicrobials. For instance, S.epi produces the protease Esp, which degrades S. aureus surface proteins to prevent adherence, and the molecule 6-HAP, which interferes with bacterial and skin cell DNA replication. Keratinocytes produce large amounts of anti-6-HAP enzymes to protect themselves, but tumor cells in skin do not, making 6-HAP protective against tumor cells.
In yet another fascinating turn of events, things really come together when skin is wounded. Bacterial cell wall products usually trigger inflammation. But in skin wounds, S.epi cell wall products instead dampen the keratinocyte inflammatory signals that result from sensing damaged host cells. The S.epi-specific T cells sense that there is a skin breach and migrate to the site, where their presence accelerates wound healing.
The prior decades of immunological research developed an array of tools and methods to uncover how our immune system protects against invading microbes. Now, the new wave of immunologists, including Dr. Belkaid, use those tools to uncover how our immune system cooperates with members of our microbiome. So far, the findings uncover an ancient relationship between mammals and microbes that protects from pathogens, cancer, and orchestrates faster wound repair. Dr. Belkaid suggests that research such as hers can lead to methods of manipulating the skin microbiota to improve skin health in areas from wound care to cancer.