EBioMedicine (Aug 2022)

Immune aging in multiple sclerosis is characterized by abnormal CD4 T cell activation and increased frequencies of cytotoxic CD4 T cells with advancing age

  • Leah Zuroff,
  • Ayman Rezk,
  • Koji Shinoda,
  • Diego A. Espinoza,
  • Yehezqel Elyahu,
  • Bo Zhang,
  • Andrew A. Chen,
  • Russell T. Shinohara,
  • Dina Jacobs,
  • Roy N. Alcalay,
  • Thomas F. Tropea,
  • Alice Chen-Plotkin,
  • Alon Monsonego,
  • Rui Li,
  • Amit Bar-Or

Journal volume & issue
Vol. 82
p. 104179

Abstract

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Summary: Background: Immunosenescence (ISC) describes age-related changes in immune-system composition and function. Multiple sclerosis (MS) is a lifelong inflammatory condition involving effector and regulatory T-cell imbalance, yet little is known about T-cell ISC in MS. We examined age-associated changes in circulating T cells in MS compared to normal controls (NC). Methods: Forty untreated MS (Mean Age 43·3, Range 18–72) and 49 NC (Mean Age 48·6, Range 20–84) without inflammatory conditions were included in cross-sectional design. T-cell subsets were phenotypically and functionally characterized using validated multiparametric flow cytometry. Their aging trajectories, and differences between MS and NC, were determined using linear mixed-effects models. Findings: MS patients demonstrated early and persistent redistribution of naïve and memory CD4 T-cell compartments. While most CD4 and CD8 T-cell aging trajectories were similar between groups, MS patients exhibited abnormal age-associated increases of activated (HLA-DR+CD38+; (P = 0·013) and cytotoxic CD4 T cells, particularly in patients >60 (EOMES: P < 0·001). Aging MS patients also failed to upregulate CTLA-4 expression on both CD4 (P = 0·014) and CD8 (P = 0·009) T cells, coupled with abnormal age-associated increases in frequencies of B cells expressing costimulatory molecules. Interpretation: While many aspects of T-cell aging in MS are conserved, the older MS patients harbour abnormally increased frequencies of CD4 T cells with activated and cytotoxic effector profiles. Age-related decreased expression of T-cell co-inhibitory receptor CTLA-4, and increased B-cell costimulatory molecule expression, may provide a mechanism that drives aberrant activation of effector CD4 T cells that have been implicated in progressive disease. Funding: Stated in Acknowledgements section of manuscript.

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