Regulatory T-cells are central hubs for age-, sex- and severity-associated cellular networks during COVID-19

Abstract

Using single-cell proteomics by mass cytometry, we investigate changes to a broad selection of over 10,000,000 immune cells in a cohort of moderate, severe, and critical Japanese COVID-19 patients and healthy controls with a particular focus on regulatory T-cells (Tregs). We find significant disruption within all compartments of the immune system and the emergence of atypical CTLA-4high CD4 T-cells and proliferating HLA-DRlowCD38high Tregs associated with critical patients. We also observed disrupted regulation of humoral immunity in COVID-19, with a loss of circulating T follicular regulatory T cells (Tfr) and altered T follicular helper (Tfh)/Tfr and plasma cell/Tfr ratios, all of which are significantly lower in male patients. Shifting ratios of CXCR4 and CXCR5 expression in B-cells provides further evidence of an autoimmune phenotype and dysregulated humoral immunity. These results suggest that Tregs are central to the changing cellular networks of a wide range of cells in COVID-19 and that sex specific differences to the balance of Tfr, Tfh and plasma cells may have important implications for the specificity of the humoral immune response to SARS-CoV-2.

Multidimensional analysis of immune cells from COVID-19 patients identified cell subsets associated with the severity at hospital admission

“…Moreover, our results align with those observed by Søndergaard et al . [ 40 ], where Treg expressing CD38 marker were increased related to COVID-19 severity. The Treg-expressing CD38 subset has been described as a Treg subset with a high immunosuppressive ability [ 41 , 42 ], and the expression of CD38, in this case, could explain the activation of the Treg and complete the list of functional markers described by Vick et al .…”

Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID

“…Adaptive immune responses are also modulated by SARS-CoV-2 infection. Several studies report decreases in CD4 + T cells, CD8 + T cells, CD4 + FoxP3 + regulatory T cells (Tregs), MAIT (CD8 + mucosal-associated invariant T) cells, γδ T cells, and αβ T cells in persons with mild or severe COVID-19 (25)(26)(27)(28). Conversely, increases in the ratio of CD4 + /CD8 + T cells, or Tregs number, have also been reported in persons with COVID-19 (29,30).…”

“…Notably, the counts of total T cells, including CD4 + and CD8 + T cells, are reduced in persons with COVID-19 and adversely associated with survival (71). Moreover, the proportion or counts of Tregs, MAIT cells, γδ T cells, and αβ T cells are correspondingly reduced in persons with mild or severe COVID-19 (25)(26)(27)(28). Strikingly, it has been reported that T cells are functionally exhausted (defined by upregulated expression of Fas, PD-1, CTLA-4, TIGIT, and TIM-3, and downregulated expression of granzyme B, IFN-γ, IL-2, and TNF) in persons with COVID-19 (31).…”