Innate Immunity and Telomeres – INNATELO

The maintenance of DNA integrity is a pivotal aspect of life. However, DNA alterations are common events that occur randomly (i.e. spontaneous hydrolysis, deamination), and are induced by cell division (errors in DNA replication), by endogenous products (e.g. reactive oxygen species) or by upon environmental assaults such as radiations, viral infection or chemical exposure. Cells respond intrinsically to the perception of DNA damage by initiating the DNA damage response (DDR) that leads to cell-cycle arrest and repair attempts. Critical shortening or chromatin alterations of telomeres also activate the DDR, thereby inducing senescence or apoptosis. In addition, DDR induction leads to extrinsic responses, illustrated by the activation of innate immune responses that remove damaged cells from the organism. However, DNA quality control mechanisms eventually fail, leading to accumulation of DNA alterations, which are associated with aging and with the development of cancers. Many unknowns remain in the description and understanding of the extrinsic genome surveillance systems.

INNATELO will dissect the mechanisms by which the integrity of organisms is kept in check by the detection of DNA alterations by the innate immune system. We will focus our studies on the detection of DNA alterations by Natural Killer (NK) cells in human and mouse via alteration of telomeric proteins. This central aim is based on ground-breaking discoveries on the role of NK cells in the detection of senescent cells and two set of recent findings by our laboratories. First, we have identified a novel molecular pathway by which NK cells recognize various tumor cell types. Second, we have shown that the dosage of the central telomere protective factor TRF2 has an impact on a cell-extrinsic program regulating innate immunity.

Specifically, we now propose to investigate:

(1) How NK cells distinguish their targets from normal cells
(2) How telomeres affect cell fate and immunity
(3) The roles of telomere factors in innate immunity.

To reach these objectives, we have built an interdisciplinary proposal involving a laboratory working on the dissection of innate immune response and a laboratory working on the biology of telomeres, with the aim to open new horizon and opportunities for research. We think that the combination of our methodologies is an illustration of the state-of-the-art platform technology that our laboratories propose to set-up in this interdisciplinary and innovative joint-venture. We also believe that our model systems designed to understand the mechanisms linking telomere dysfunction and innate immunity in tumor suppression will open a new field of investigations on the role of telomere-dependent immune responses in development, tissue homeostasis and aging.