T-bet, the new bridgehead of the innate immune response

The team of Jacinta Bustamante, a pediatrician and immunologist, senior lecturer at Université de Paris at the Center for the Study of Immune Deficiencies at Hôpital Necker-Enfants malades and head of the MSMD group in the laboratory of Jean-Laurent Casanova, has made considerable clinical and immunological progress by progressively discovering the mutations at the origin of the Mendelian Predisposition Syndrome (MSMD). Jean-Laurent Casanova, also a pediatrician, is a professor at Université de Paris and at the Rockefeller University/Howard Hughes Medical Institute in New York, and co-founder of the Laboratory of Human Genetics of Infectious Diseases, an international laboratory of Inserm organized in two branches, one at the Rockefeller in New York and the other at the Imagine-Hôpital Necker Enfants Malades-AP-PH While environmental mycobacteria or the BCG vaccine generally do not cause disease, some infected individuals do develop extremely serious manifestations. In 1996, Jean-Laurent Casanova and his team shed light on these serious reactions, which can even lead to death: they are due to a genetic alteration that renders the immune mechanisms that are supposed to protect them against this specific type of microorganism defective. Jacinta Bustamante took the lead in this work in 2008. Genetics therefore influences the ability to respond to infectious diseases. Since then, the evidence in this sense has been accumulating and extending to other diseases such as influenza, tuberculosis and the latest one: COVID-19.

MSMD: a mutation that changes everything

For MSMD, no less than 31 genetic defects have been uncovered, related to mutations in 16 genes. They consistently alter the same mechanism of the immune system, namely the ability to produce or respond to interferon ɣ (IFN-ɣ).

Unlike other interferons, which are primarily anti-viral cytokines and are synthesized by all cells in the body, IFN-ɣ is synthesized by lymphocytes and primarily activates phagocytic cells. It is a key player in the immune system's response to intramacrophageal infections, especially mycobacterial. This cytokine, synthesized by several types of lymphocytes, both those of innate immunity, the 1st line of defense that is set up in the body, and those of adaptive immunity, a response that takes longer to be triggered but is better targeted. "IFN-ɣ coordinates, as it were, the defense reactions following a mycobacterial attack," explains Jean-Laurent Casanova. It ensures the proper flow of information and triggers the activation of other cells of both innate and adaptive immunity."

The severity of the clinical presentation of Mendelian predisposition syndrome to mycobacterial infections or MSMD depends on the genetic mutations involved and their ability to modulate IFN-ɣ activity. Dr. Rui Yang in Jacinta Bustamante's group has just discovered a new genetic mutation responsible for a severe form of mycobacterial infection and thus lifts the veil a little more on the mechanisms involved in this type of immune response. The mutation affects the transcription factor T-bet (TBX21), a gene that activates the expression of other genes. In this case, the mutation reduces the production of IFN-ɣ by natural killer (NK) cells, lymphocytes of the innate immune system capable of killing infected cells, and its counterpart, iNK. In contrast, no effect on the adaptive immune response is observed, suggesting the existence of mechanisms compensating for this failure.

T-bet is therefore essential for the initiation of the innate response involving NK and iNK cells. In contrast, its role in the mycobacteria-targeted adaptive response appears to be redundant with another mechanism and the latter is therefore not affected. A surprise of this observation is that T-bet was, on the basis of work conducted in mice, until now considered a key player in IFN-ɣ production by T cells of adaptive immunity. This work in humans shows that T-bet is essential for the production of IFN-ɣ by innate lymphocytes and not by adaptive lymphocytes.

This discovery represents a step forward in the understanding of MSMD but also in the mechanisms of the immune response.

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Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria