MICAgen Mice Recapitulate the Highly Restricted but Activation-Inducible Expression of the Paradigmatic Human NKG2D Ligand MICA

Abstract

of MICA-specific antibodies. Such immunotolerance for the xenoantigen MICA ideally suits MICAgen mice for anti-MICA-based immunotherapies. Altogether, MICAgen mice represent a valuable model to study regulation, function, disease relevance, and therapeutic targeting of MICA in vivo.

NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells

“…25,32,33,36 MICA transgenic mice bypass this limitation and will be invaluable to assess the safety profile of NKG2D-based therapies. 58 Alternatively, non-human primates can also be utilised in such studies. Of note, chimeric NKG2D receptor T cells were well tolerated by patients with haematological malignancies in a clinical trial reported recently, thus serving as the first evidence of the safety of an NKG2D-based immunotherapy.…”

“…Until now, the antibodies that inhibit MICA/B shedding or neutralise soluble MICA/B were administered to mice engrafted with MICA/B + tumors but since mice do not have the MICA/B genes they do not serve to toxicological studies 25,32,33,36 . MICA transgenic mice bypass this limitation and will be invaluable to assess the safety profile of NKG2D‐based therapies 58 . Alternatively, non‐human primates can also be utilised in such studies.…”

“…56 Of note, a MICA transgenic mouse strain shows robust expressions of MICA mRNA and protein in the small intestine plus other organs including the lungs, skin and bone marrow from healthy mice. 58 The molecular mechanism that controls MICA expression in these organs is unknown, but it is expected to be associated with cellular stress. For example, enterocytes express MICA in CD potentially as a result of cellular stress caused by tissue damage and loss of tissue integrity in an environment highly colonised by microorganisms that may cause infection; this speculation still has to be verified experimentally.…”

“…The blood sera from patients with active CD have higher concentrations of soluble MICA compared to control and CD patients on a gluten‐free diet 56 . Of note, a MICA transgenic mouse strain shows robust expressions of MICA mRNA and protein in the small intestine plus other organs including the lungs, skin and bone marrow from healthy mice 58 . The molecular mechanism that controls MICA expression in these organs is unknown, but it is expected to be associated with cellular stress.…”

KIR+ CD8+ T Lymphocytes in Cancer Immunosurveillance and Patient Survival: Gene Expression Profiling

“…Other receptors, such as NKG2D, play decisive roles in tumor immune response. NKG2D is a potent activating immunoreceptor expressed on nearly all cytotoxic lymphocytesthat promotes cytotoxicity against cells expressing NKG2Dligands (MICA/B and ULBP1-6), which are induced bycellular stress, viral infection, or malignant transformation [ 5 ]. Experimental mice models have shown that NKG2D/ligand interactions on NK cells can induce a strong secretion of IL-2 and IFN-γ,which contribute to suppressing tumor growth by modulating tumor microenvironment [ 6 ].…”