Your body is full of MAIT cells, or mucosal-associated invariant T cells. They are a specialized type of T lymphocyte that responds to various bacteria and fungi. These cells, however, are not your usual T cells. Unlike other types of T cells, MAIT cells don’t abide by the conventional rules that govern T cell development. Yet, somehow, they mature, and become part of the immune repertoire. Although recent years brought significant advancements in our understanding of MAIT cell biology, the maturation of these cells largely remained a mystery. Now, a 2019 study published in Science from the group of Olivier Lantz sheds some light on the development of these curious T cells.

The T cell division

One of the major functions of T cells is to protect an organism against microorganisms; they are one of the cellular divisions of immune “law enforcement”. Not unlike conventional law enforcement, the T cell sector is governed by specific rules. For one, the T cell soldiers should participate in the defense responses only when presented with specific physical evidence of an invasion—a protein sample derived from the invading pathogen. Moreover, the handing in of that evidence should be carried out by another division, a type of cells that act like informants. Interaction of these cells must occur in the presence of a specific molecule known as the MHC. Only when the protein sample from the pathogen is passed to the T cells by the informants via this particular MHC molecule, can the T cells kick into an action mode. To execute these rules all T cells must undergo rigorous training. 

Traditional T cell training

The T cell training occurs in the thymus. The early stages of the development of a functional T cell involve specialization—every “naive recruit” must develop a T cell receptor, a molecular sensor that recognizes a unique antigen. To allow successful cooperation with the informants these sensors should only recognize pathogens’ protein samples when an MHC molecule is present. Only those T cells which receptors meet those requirements are selected for duty.

And so, as the T cell-in-training progress through the developmental process; it undergoes tests to ensure those prerequisites are met. These tests are based on simulations of sorts, where cells in the thymus present “dummy” sample proteins on MHC molecules for maturing T cells. If the T cell reacts appropriately, it will be deemed a success and become part of the T cell division. If it fails to respond in a correct manner, however, it will not only “flunk” but also die.

MAIT cells break the rules

For decades researchers believed in the universality of the rules that govern T cells. In the early 1990s, however, the world of immunology was shaken by the discovery of a unique population of T cells, later dubbed MAIT cells, to which these rules did not apply. Instead of recognizing specific antigens, these T cells turned out to sense metabolites of vitamin B2, organic small molecules, rather than proteins. Moreover, rather than relying on MHC molecules, they use a distinct molecule known as MHC-related molecule 1 (MR1). Despite these unique traits, however, these cells somehow successfully “graduated” from the training and were dispatched to defend the organism against invasion.

Bacteria help MAIT cells’ development

The researchers from the Curie Institute uncovered peculiar aspects of the development of MAIT cells. Intrigued by their earlier discovery of lower numbers of MAIT cells in mice that lack commensal bacteria, they had a hunch that the beneficial bugs played into the development of these cells. Indeed, by investigating the specific stages of MAIT cells’ development in the thymi of “bacteria-free” mice, they discovered the microbes were essentials for the cells to complete their training. But how do these bacterial residents of the gut and the skin affect a process that happens inside an organ hidden deep within the chest? It seemed unlikely that the bugs themselves traveled all the way to the thymus. Could it be, though, that they produced a soluble molecule that traversed that distance and played a role in MAIT cell maturation? 

With that question in mind, it wasn’t hard to conceive of a potential mechanism—small molecule by-products of microbial metabolic processes could be those soluble molecules. For one, vitamin metabolism is one of the fortes of commensals. And it is none other the metabolites of vitamin B2 that the T cell receptor of MAIT cells recognizes. Perhaps, rather than being tested for their response to the sample proteins on MHC molecules, MAIT cells are tested for appropriate responses to microbially-provided vitamin B2 metabolites. 

Indeed, when Legoux et al. re-colonized the mice lacking bacteria with microbes incapable of producing that vitamin B2 metabolites, the MAIT cells didn’t fully develop. On the other hand, when they provided the bacteria-free mice with bugs capable of generation of the particular molecules, maturation of the MAIT cells was completely restored. This was also the case when the researchers directly administered the vitamin B2 metabolites to the mice; the MAIT cells developed normally. But that’s not all. When Legoux et al. analyzed the thymi of the mice injected with the metabolite, they detected the molecule in the thymus on none other than the MR1-expressing cells, the cells most likely to support the maturation of MAIT cells. Bacterial products found in the organ thought to be “impermeable” to such outside influences – talk about breaking the rules! 

The discoveries reported by Legoux et al. revolutionize the study of T cell biology; it’s the first time a microbial product has been shown to make its way to the thymus and play such a crucial role in the development of T cells. Who would have thought that a “foreigner” would play such an important role in the training of our T cell soldiers. 

Reference: Legoux F, et al. (2019) Microbial metabolites control the thymic development of mucosal-associated invariant T cells. Science. 366(6464):494-9.

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