Water channel aquaporin 4 is required for T cell receptor mediated lymphocyte activation

Nicosia, Michael; Lee, Juyeun; Beavers, Ashley; Kish, Danielle D.; Farr, George W.; McGuirk, Paul R.; Pelletier, Marc F.; Lathia, Justin D.; Fairchild, Robert L.; Valujskikh, Anna

doi:10.1093/jleuko/qiad010

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…In previous work, we did not detect AQP4 protein or mRNA in WT murine peripheral T cells ( 51 ). However, one group reported that T cell AQP4 deficiency reduced TCR-mediated signaling, although they did not detect any change in thymocyte subsets ( 52 ). It should be recognized that it was the AQP4-specific T cells from AQP4 −/− but not WT mice that induced CNS autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity

Sagan

Moinfar

Moseley

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4 −/− ), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4 −/− mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell–dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.

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Section: Discussionmentioning

confidence: 99%

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity

Sagan

Moinfar

Moseley

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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T cells go with the flow: aquaporin 4 is required for full T-cell activation

Morley

2023

Journal of Leukocyte Biology

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Sepsis Course and Outcome Depends on the Genetic Variant in the 3`-Region of Aquaporin 4 Gene <i>AQP4</i> and Comorbidities

Chumachenko,

Grigoriev,

Cherpakov

et al. 2023

Obŝaâ reanimatologiâ

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Aquaporins 4 and 5 are proteins that form water channels in the cell membrane, participate in the transfer and migration of immune cells, being expressed on many cell types including CNS astrocytes, kidney cells, lungs, and the immune system. We have previously shown that AQP5 genetic polymorphism is associated with different outcomes of abdominal sepsis. Since another common aquaporin protein, AQP4, is also expressed on the surface of immunocompetent cells, determining cell motility, it was suggested that AQP4 may also be important in the pathogenesis of sepsis, and that AQP4 polymorphism may predetermine sepsis severity and outcome. AQP4 rs1058427 genetic polymorphism has not been studied earlier.The aim of the study was to determine the effects of region 3` polymorphism in the AQP4 gene on the clinical course and outcome of sepsis.Materials and methods. The prospective study included 290 ICU patients from three clinical hospitals in Moscow aged 18-75 years with clinical signs of sepsis (SEPSIS-3, 2016).Results. It was found that the minor T allele of the AQP4 rs1058427 gene provides strong protection against septic shock, as among GG genotype carriers septic shock developed in 66%, but in presence of the minor T allele this number dropped two-fold (p=0.009, Fisher’s exact test, OR=1.99, 95% CI: 1.12-3.55, n=290). There was a significant association between AQP4 rs1058427 genetic polymorphism and 30-day hospital mortality in a subgroup of patients with more severe organ dysfunction and higher comorbidity burden (cardiovascular diseases, type II diabetes mellitus) requiring extracorporeal treatment modalities and ventilator support for 5 or more days (n=66). Carriers of the minor T allele showed better survival rates as compared AQP4 rs1058427 GG genotype carriers (5 deaths out of 10 and 47 deaths out of 56, respectively, p=0.003, Fisher’s exact test, n=66, OR=5.22, 95% CI: 1.25-21.82, P=0.009, log-rank criterion).Conclusion. The minor AQP4 rs1058427 T allele is associated with protection against septic shock and better survival in sepsis in a group of ICU patients with high comorbidity burden requiring extracorporeal life support interventions.

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Water channel aquaporin 4 is required for T cell receptor mediated lymphocyte activation

Cited by 3 publications

References 47 publications

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity

T cells go with the flow: aquaporin 4 is required for full T-cell activation

Sepsis Course and Outcome Depends on the Genetic Variant in the 3`-Region of Aquaporin 4 Gene <i>AQP4</i> and Comorbidities

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