PT  - JOURNAL ARTICLE
AU  - Carmena Moratalla, Ana
AU  - Carpentier Solorio, Yves
AU  - Lemaitre, Florent
AU  - Farzam-kia, Negar
AU  - Levert, Annie
AU  - Zandee, Stephanie E.J.
AU  - Lahav, Boaz
AU  - Guimond, Jean Victor
AU  - Haddad, Elie
AU  - Girard, Marc
AU  - Duquette, Pierre
AU  - Larochelle, Catherine
AU  - Prat, Alexandre
AU  - Arbour, Nathalie
TI  - Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8<sup>+</sup> T-Cell Behaviors
AID  - 10.1212/NXI.0000000000001119
DP  - 2022 Jan 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e1119
VI  - 9
IP  - 1
4099  - http://nn.neurology.org/content/9/1/e1119.short
4100  - http://nn.neurology.org/content/9/1/e1119.full
SO  - Neurol Neuroimmunol Neuroinflamm2022 Jan 01; 9
AB  - Background and Objectives We posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular stressors inducing the expression of UL16-binding protein 4 (ULBP4), the only detectable NKG2DL. Finally, we evaluate the impact of ULBP4 on functions such as cytokine production and motility by CD8+ T lymphocytes, a subset largely expressing NKG2D, the cognate receptor.Methods Human postmortem brain samples and CSF from patients with MS and controls were used to evaluate NKG2DL expression. In vitro assays using primary cultures of human astrocytes and neurons were performed to identify stressors inducing ULBP4 expression. Human CD8+ T lymphocytes from MS donors and age/sex-matched healthy controls were isolated to evaluate the functional impact of soluble ULBP4.Results We detected mRNA coding for the 8 identified human NKG2DLs in brain samples from patients with MS and controls, but only ULBP4 protein expression was detectable by Western blot. ULBP4 levels were greater in patients with MS, particularly in active and chronic active lesions and normal-appearing white matter, compared with normal-appearing gray matter from MS donors and white and gray matter from controls. Soluble ULBP4 was also detected in CSF of patients with MS and controls, but a smaller shed/soluble form of 25 kDa was significantly elevated in CSF from female patients with MS compared with controls and male patients with MS. Our data indicate that soluble ULBP4 affects various functions of CD8+ T lymphocytes. First, it enhanced the production of the proinflammatory cytokines GM-CSF and interferon-γ (IFNγ). Second, it increased CD8+ T lymphocyte motility and favored a kinapse-like behavior when cultured in the presence of human astrocytes. CD8+ T lymphocytes from patients with MS were especially altered by the presence of soluble ULBP4 compared with healthy controls.Discussion Our study provides new evidence for the involvement of NKG2D and its ligand ULBP4 in MS pathology. Our results point to ULBP4 as a viable target to specifically block 1 component of the NKG2D pathway without altering immune surveillance involving other NKG2DL.BBB=blood-brain barrier; CA=chronic active; EAE=experimental autoimmune encephalomyelitis; ER=endoplasmic reticulum; GBM=glioblastoma multiforme; GFAP=glial fibrillary acidic protein; GM-CSF=granulocyte-macrophage colony-stimulating factor; IFNγ=interferon-γ; MIC=major histocompatibility complex class I chain-related protein; MICA=major histocompatibility complex class I chain-related protein A; MICB=major histocompatibility complex class I chain-related protein B; MS=multiple sclerosis; MULT1=murine UL16-binding proteinlike transcript 1; NAGM=normal-appearing gray matter; NAWM=normal-appearing white matter; NK=natural killer; NKG2D=natural killer group 2D; OND=other neurologic disorder; PPMS=primary progressive MS; rhULBP4=recombinant human ULBP4; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS; TNF=tumor necrosis factor; ULBP4=UL16-binding protein 4