People with diabetes mellitus are more vulnerable to viral infections including influenza and the ongoing COVID-19 pandemic. Fatal pneumonia and cytokine storm is a contributor to the mortality. We hypothesized that aberrant glycemic control induces an immune dysregulation, which compromises the anti-viral immunity and promotes inflammation by altering the balance of the protective T-regulatory cells (Tregs) and IL-17 responses. Indeed, comparison of the peripheral blood lymphocytes in a limited cohort of healthy controls (HC; n=4) and people with diabetes (n=9) showed profound immune dysregulation. As compared to HC (66±21 x10^3/ml), the number of circulating Tregs were significantly (p<0.0001) reduced in diabetes group (15±2 x10^3/ml). Compared to HC, the proportion of IL-17 producing CD4 and CD8 T-cells was remarkably increased in the diabetes group at baseline as well as upon ex-vivo stimulation. A comparison of the ratio of IFNγ to IL-17 producing CD8 T-cells showed a significant bias towards reduced IFNγ and enhanced IL-17 production in the diabetes group (4.7±1.7) as compared to the HC (35±4). Similarly, comparison of the ratio of Tregs and Th1 to Th17 cells was also significantly biased towards reduced Treg and Th1 cells, and an exacerbated Th17 response in diabetes group as compared to the HC. Meta-analysis confirmed a significant positive correlation between HbA1c levels and the exacerbated IL-17 to IFNg ratios in CD4 (R2=0.7, p=0.0008) as well as CD8 (R2=0.6, p=0.002) cells.

In summary, altered glycemic control, as indicated by higher HbA1c levels, significantly correlates with compromised IFNg production in the CD8 and Th1 cells, which is important for anti-viral immunity, as well as a marked proinflammatory shift shown as reduced Tregs levels and enhanced IL-17 production by both CD4 and CD8 cells. This immune-dysregulation in diabetes may thus contribute to a greater susceptibility to viral infections and infection-induced pathology.

Disclosure

V. Sabapathy: Stock/Shareholder; Self; 10x Genomics, Apple, AstraZeneca, Bayer U. S., Gilead Sciences, Inc. M. Dogan: None. R. Venkatadri: None. R. Arbab: None. J. Z. Ma: None. A. Basu: None. R. Basu: None. R. Sharma: Other Relationship; Self; SlateBio Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104963); University of Virginia

© 2021 by the American Diabetes Association
2021
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