Carnitine and kynurenine drive CD8⁺T cell senescence: a bidirectional Mendelian randomization study elucidates novel mechanisms of uremia-associated immune dysregulation

To systematically investigate the bidirectional causal relationship between 10 uremia-related toxins and metabolites and CD8⁺ T cell senescence phenotypes using Mendelian randomization (MR).

A bidirectional MR analysis was performed using genome-wide association studies (GWAS) data to extract single nucleotide polymorphisms closely associated with 10 uremia-related toxins and metabolites and CD8⁺ T cell senescence phenotypes as instrumental variables. The primary analytical method was inverse variance weighting (IVW), supplemented by MR-Egger, weighted median, simple mode, and weighted mode. The robustness and potential pleiotropy of the results were verified by sensitivity analyses including Cochran's Q test, MR-Egger intercept test, MR-PRESSO and leave-one-out analysis.

MR analysis showed that carnitine level was positively associated with the proportion of terminally differentiated CD8⁺ T cells (IVW: β=1.71, 95%CI: 0.59 to 2.83, P=0.003), the proportion of CD45 RA⁺CD28^-CD8⁺T cells (IVW: β=2.23, 95%CI: 0.65 to 3.80, P=0.006), and the proportion of CD28^-CD8⁺T cells (IVW: β=1.13, 95%CI: 0.11 to 2.15, P=0.030). Kynurenine level also showed a significant positive association with the proportion of terminally differentiated CD8⁺T cells (IVW: β=1.69, 95%CI: 0.57 to 2.82, P=0.0003), while IL-6 level presented a positive correlation with the proportion of CD28^-CD8⁺T cells (IVW: β=0.28, 95%CI: 0.03 to 0.53, P=0.026) and the proportion of CD45 RA⁺CD28^-CD8⁺T cells (IVW: β=0.41, 95%CI: 0.02 to 0.79, P=0.04). N², N²-dimethylguanosine level was positively correlated with CD45 RA⁺CD28^-CD8⁺T cell absolute count (IVW: β=2.53, 95%CI: 0.51 to 4.55, P=0.014). Reverse MR analysis revealed an increase in the absolute count of CD45 RA⁺CD28^-CD8⁺T cells was causally associated with a reduction in carnitine levels (IVW: β=-0.00003, 95%CI: -0.000062 to 0.000004, P=0.024). All sensitivity analyses supported the robustness of the main findings.

There are bidirectional causal associations between uremiarelated toxins and metabolites and CD8⁺T cell senescence, providing novel causal insights and potential intervention targets for immune dysfunction in uremic patients.