Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis
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Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis. / Winschel, Ingo; Willing, Anne; Engler, Jan Broder; Walkenhorst, Mark; Meurs, Nina; Binkle-Ladisch, Lars; Woo, Marcel S; Pfeffer, Lena Kristina; Sonner, Jana K; Borgmeyer, Uwe; Hagen, Sven Hendrik; Grünhagel, Benjamin; Claussen, Janna M; Altfeld, Marcus; Friese, Manuel A.
in: BIOL SEX DIFFER, Jahrgang 15, Nr. 1, 15.05.2024, S. 41.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis
AU - Winschel, Ingo
AU - Willing, Anne
AU - Engler, Jan Broder
AU - Walkenhorst, Mark
AU - Meurs, Nina
AU - Binkle-Ladisch, Lars
AU - Woo, Marcel S
AU - Pfeffer, Lena Kristina
AU - Sonner, Jana K
AU - Borgmeyer, Uwe
AU - Hagen, Sven Hendrik
AU - Grünhagel, Benjamin
AU - Claussen, Janna M
AU - Altfeld, Marcus
AU - Friese, Manuel A
N1 - © 2024. The Author(s).
PY - 2024/5/15
Y1 - 2024/5/15
N2 - BACKGROUND: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated.METHODS: In this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression.RESULTS: Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction.CONCLUSIONS: Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.
AB - BACKGROUND: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated.METHODS: In this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression.RESULTS: Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction.CONCLUSIONS: Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.
KW - Animals
KW - Female
KW - Male
KW - Humans
KW - 12E7 Antigen/metabolism
KW - Multiple Sclerosis/immunology
KW - Sex Characteristics
KW - T-Lymphocytes/metabolism
KW - Mice, Inbred C57BL
KW - Jurkat Cells
KW - Spleen/metabolism
KW - Species Specificity
KW - Mice
KW - Encephalomyelitis, Autoimmune, Experimental/immunology
KW - Mice, Knockout
KW - Adult
U2 - 10.1186/s13293-024-00618-y
DO - 10.1186/s13293-024-00618-y
M3 - SCORING: Journal article
C2 - 38750588
VL - 15
SP - 41
JO - BIOL SEX DIFFER
JF - BIOL SEX DIFFER
SN - 2042-6410
IS - 1
ER -