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Regulation of immune responses and autoimmunity by activating and inhibitory NK receptors expressed by T lymphocytes: role of ITAM versus ITIM signal balance

Final Activity Report Summary - LY49-AUTOIMMUNITY (Regulation of immune responses and autoimmunity by activating and inhibitory NK receptors expressed by T lymphocytes ...)

In the immune system, the balance between activating signals (i.e. ITAM receptors) and inhibitory signals (i.e. ITIM receptors) normally gives rise to an adequate and fine-tuned response against pathogens. Thus, the response of the effector killing cells can be modulated, to avoid a too long or too strong response that may be deleterious for the organism. This balance through ITAM and ITIM receptors is important for the biology of NK cells, the killer cells of innate immunity. Recent studies have shown that some activating NK receptors (ITAM receptor) can be expressed by T cells particularly in case of chronic inflammatory disorders or autoimmunity.

To analyse if expression of NK ITAM-receptors can remove some specificity to the adaptive immunity, we used a mouse model, which aberrantly express a NK ITAM-receptor Ly49D on their T cells. In this project, we could determine that engagement of Ly49D on T cells triggers a wide range of activities, normally restricted to TCR engagement (TCR is the classical activating receptor of T cells). The T cells are able to produce inflammatory soluble factors, to survive and to proliferate. Most importantly, Ly49D expressing T cells can kill tumour cells that express the ligand recognised by Ly49D in vitro and in vivo. Thus T cells expressing activating NK receptors (receptors from the innate arm of the immune system) acquire a new autonomous activation system, totally independent of the specificity of the TCR, losing partially their features of cells from the adaptive immune system.

The results generated in our study can partially explain the uncontrolled killing function of T cells in chronic inflammatory disorders or autoimmunity, because of the loss of TCR specificity. In addition, we demonstrate that activating NK receptors expressed by T cells can be used to enhance killing in an immunotherapy strategy against cancer.