Genetic Disruption at the CIP2A Locus Modulates T Cell Responses and Attenuates Experimental Autoimmune Encephalomyelitis
- 1University of Turku
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) driven by pathogenic T cell-mediated inflammation. Fingolimod (FTY720), an approved therapy for MS, is an established activator of protein phosphatase 2A (PP2A). However the contribution of PP2A in autoimmune neuroinflammation remains incompletely understood. Here, we addressed this question using experimental autoimmune encephalomyelitis (EAE), a murine model of MS, in mice carrying a genetic disruption of the locus encoding cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A. Mice with disruption of the CIP2A locus, the knock out (KO) mice, exhibited attenuated EAE severity compared with wild-type (WT) controls. Histological and flow-cytometric analyses revealed markedly reduced infiltration of mononuclear cells, including CD4 and CD4CXCR6 encephalitogenic T cells, in the CNS of diseased KO mice. Reduced numbers of these T cell populations were also observed in peripheral lymphoid organs of the Cip2a-deficient mice during EAE, while T cell abundance was comparable under steady-state conditions, suggesting impaired activation-induced expansion rather than altered homeostasis or migration. Single-cell RNA sequencing of CNS and lymph node immune cells revealed changes in cell-type abundance and gene expression. Notably, Il17a expression was reduced in CNS CD8+ T cells and showed a similar trend in {gamma}{delta} T cells. Together, our findings reveal that genetic disruption at the CIP2A locus attenuates EAE, possibly by limiting the expansion and accumulation of encephalitogenic T cell populations in CNS. These results identify the CIP2A locus as a previously unrecognized regulator of T cell-driven autoimmune neuroinflammation and provide new insights into mechanisms that restrain pathogenic T cell responses during EAE.
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BibTeX
@misc{khan2026genetic,
title = {{Genetic Disruption at the CIP2A Locus Modulates T Cell Responses and Attenuates Experimental Autoimmune Encephalomyelitis}},
author = {M. M. Khan and I. Starskaia and E. Rydgren and S. Junttila and J. Smolander and M. H. Khan and R. Biradar and R. Kattelus and A. Ahtikoski and M. Gardberg and M. M. Banday and U. Riyaz and J. Khabbal and E. Yatkin and L. Tian and P. P. Ho and T. Lönnberg and L. L. Elo and L. Steinman and J. Westermarck and O. Rasool and R. Lahesmaa and U. U. Kalim},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.746989},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.746989v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Genetic Disruption at the CIP2A Locus Modulates T Cell Responses and Attenuates Experimental Autoimmune Encephalomyelitis
AU - M. M. Khan
AU - I. Starskaia
AU - E. Rydgren
AU - S. Junttila
AU - J. Smolander
AU - M. H. Khan
AU - R. Biradar
AU - R. Kattelus
AU - A. Ahtikoski
AU - M. Gardberg
AU - M. M. Banday
AU - U. Riyaz
AU - J. Khabbal
AU - E. Yatkin
AU - L. Tian
AU - P. P. Ho
AU - T. Lönnberg
AU - L. L. Elo
AU - L. Steinman
AU - J. Westermarck
AU - O. Rasool
AU - R. Lahesmaa
AU - U. U. Kalim
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.746989
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.746989v1
AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) driven by pathogenic T cell-mediated inflammation. Fingolimod (FTY720), an approved therapy for MS, is an established activator of protein phosphatase 2A (PP2A). However the contribution of PP2A in autoimmune neuroinflammation remains incompletely understood. Here, we addressed this question using experimental autoimmune encephalomyelitis (EAE), a murine model of MS, in mice carrying a genetic disruption of the locus encoding cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A. Mice with disruption of the CIP2A locus, the knock out (KO) mice, exhibited attenuated EAE severity compared with wild-type (WT) controls. Histological and flow-cytometric analyses revealed markedly reduced infiltration of mononuclear cells, including CD4 and CD4CXCR6 encephalitogenic T cells, in the CNS of diseased KO mice. Reduced numbers of these T cell populations were also observed in peripheral lymphoid organs of the Cip2a-deficient mice during EAE, while T cell abundance was comparable under steady-state conditions, suggesting impaired activation-induced expansion rather than altered homeostasis or migration. Single-cell RNA sequencing of CNS and lymph node immune cells revealed changes in cell-type abundance and gene expression. Notably, Il17a expression was reduced in CNS CD8+ T cells and showed a similar trend in {gamma}{delta} T cells. Together, our findings reveal that genetic disruption at the CIP2A locus attenuates EAE, possibly by limiting the expansion and accumulation of encephalitogenic T cell populations in CNS. These results identify the CIP2A locus as a previously unrecognized regulator of T cell-driven autoimmune neuroinflammation and provide new insights into mechanisms that restrain pathogenic T cell responses during EAE.
ER -