Reduced IFN-γ-expressing SARS-CoV-2 specific CD4+ T cells and transient CD8 + T cell activation associate with higher HOMA-IR 1-year post COVID-19 in obese individuals.

Insulin resistance is one of the metabolic complications of COVID-19. Our previous study showed a 22% median increase in homeostasis model assessment-estimated insulin resistance (HOMA-IR) in obese individuals at 12 months post-infection compared to acute infection. This study aimed to investigate the association between various subsets of IFN-γ-expressing SARS-CoV-2-specific CD4⁺ and CD8⁺ T cells and insulin resistance in convalescent COVID-19 patients over a one-year post-infection follow-up period. A nested case control study of 47 COVID-19 patients was followed for 12 months post-infection and categorized into three groups based on obesity and changes in HOMA-IR at one year: non-obese without increased HOMA-IR (NO), obese without increased HOMA-IR (O), and obese with increased HOMA-IR (O-IR). Increased HOMA-IR was defined as a HOMA-IR ratio (12-month to 1-month convalescence phase) > 1.21. To study antigen-specific responses, peripheral blood mononuclear cells (PBMC)s were isolated and incubated with SARS-CoV-2 peptide antigens for 24 h. Intracellular IFN-γ expression, as well as exhaustion and senescence markers, in various CD4⁺ and CD8⁺ T cell subsets were measured by flow cytometry. The abundance of IFN-γ-expressing SARS-CoV-2-specific CD4⁺ T cells was lower in the O-IR group compared to individuals without increased HOMA-IR during the 9th to 12th months of follow-up (p < 0.05). Conversely, the O-IR group exhibited a mild but significantly higher IFN-γ-expressing CD8⁺ T cells from the 3rd to the 9th month of the convalescence phase (p < 0.05). A reduced proportion of functional (PD-1^-CD57^-) SARS-CoV-2-specific T cells was observed in O-IR group. Furthermore, the reduced proportion of functional SARS-CoV-2-specific CD4⁺ T cells observed within 12 months of convalescence were have significant weak negative correlation with HOMA-IR ratio as well as HOMA-IR value. Our study demonstrates that obese individuals with increased HOMA-IR exhibited a reduced proportion of IFN-γ-expressing functional SARS-CoV-2-specific CD4⁺ T cells one year after COVID-19. This reduction, along with the decreased frequencies of both functional CD4⁺ within 12 months of convalescence, suggests a potential association between impaired SARS-CoV-2-specific T cell function and the development of insulin resistance following COVID-19. These findings warrant further investigation.